Methods of treating oral mucositis

ABSTRACT

Methods and kits for treating oral mucositis are disclosed. The treatment comprises administering to a patient in need thereof a Reactive Oxygen Species scavenger in a pharmaceutically acceptable formulation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. patent application Ser. No.16/802,916 filed on Feb. 27, 2020, which claims priority from U.S.patent application Ser. No. 15/841,586 filed on Dec. 14, 2017, now U.S.Pat. No. 10,610,533, which claims priority from U.S. patent applicationSer. No. 11/871,848 filed on Oct. 12, 2007, now U.S. Pat. No. 9,855,279,which claims priority from U.S. Provisional Application Ser. No.60/829,291 filed Oct. 12, 2006, each of which are incorporated herein byreference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not Applicable.

INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A COMPACT DISC

Not Applicable.

BACKGROUND OF THE INVENTION 1. Field of the Invention

This invention relates generally to the treatment of oral mucositis and,more particularly, to methods for treating oral mucositis with aReactive Oxygen Species (“ROS”) scavenger. The compositions and methodsare useful in treating oral mucositis.

2. Description of Related Art

Oral ulcerative mucositis is a common, painful, dose-limiting toxicityof drug and radiation therapy for cancer (1). The disorder ischaracterized by breakdown of the oral mucosa that results in theformation of ulcerative lesions. In granulocytopenic patients, theulcerations that accompany mucositis are frequent portals of entry forindigenous oral bacteria often leading to sepsis or bacteremia (2).Mucositis occurs to some degree in more than one third of patientsreceiving anti-neoplastic drug therapy (3). The frequency and severityare significantly greater among patients who are treated with inductiontherapy for leukemia or with many of the conditioning regimens for bonemarrow transplant (4). Among these individuals, moderate to severemucositis can occur in more than three-quarters of patients. Moderate tosevere mucositis occurs in virtually all patients who receive radiationtherapy for tumors of the head and neck and typically begins withcumulative exposures of 15 Gy and then worsens as total doses of 60 Gyor more are reached (1-4).

Clinically mucositis progresses through three stages:

1. Atrophic changes accompanied by painful mucosal erythema, which canrespond to local anesthetics.2. Painful ulceration with pseudomembrane formation and, in the case ofmyelosuppressive treatment, potentially life-threatening sepsis,requiring antimicrobial therapy. Pain is often of such intensity as torequire parenteral narcotic analgesia.3. Spontaneous healing, occurring about 2-3 weeks after cessation ofanti-neoplastic therapy.

Standard therapy for mucositis is predominantly palliative, includingapplication of topical analgesics such as lidocaine and/or systemicadministration of narcotics and antibiotics. At present, the onlyapproved treatment for oral mucositis is palifermin (Kepivance) which isa member of the fibroblast growth factor (FGF) superfamily of molecules.Palifermin's approval is limited to the treatment of oral mucositis inthe patients undergoing conditioning regimens prior to hematopoieticstem cell transplants for the treatment of hematologic malignancies.

The complexity of mucositis as a biological process has only beenrecently appreciated (5-7). It has been suggested that the conditionrepresents a sequential interaction of oral mucosal cells and tissues,reactive oxygen species, pro-inflammatory cytokines, mediators ofapoptosis and local factors such as saliva and the oral microbiota.While epithelial degeneration and breakdown ultimately result in mucosalulceration, it appears that the early changes associated withradiation-induced mucosal toxicity occur within the endothelium, andconnective tissue of the submucosa. For example, electron microscopicevaluation of mucosa within 1 week of radiation shows damage to bothendothelium and connective tissue, but not epithelium. It appears thatthe overall mechanism for mucositis development is similar for bothradiation and chemotherapy (8).

Recently, a superoxide dismutase mimetic, M40403, was shown to beeffective in an animal models of inflammation (Salvemini et al., Science286:304-306, 1999) and, more specifically, in an animal model ofrheumatoid arthritis (Salvemini et al., Arthritis & Reumatism44:2909-2921, 2001). Nevertheless, treatment of oral mucositis usingM40403 has neither been reported nor suggested.

BRIEF SUMMARY OF THE INVENTION

The present teachings provide methods for treating oral mucositis. Amethod comprises administering administering to a patient in needthereof, a superoxide dismutase mimetic. In accordance with one aspectof the invention, the superoxide dismutase mimetic can be represented bythe formula:

wherein

(i) R₁, R′₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇, R′₇, R₆,R′₈, R₉, R′₉, R₁₀, and R′₁₀ are independently:

(i^(a)) hydrogen; or

(i^(b)) a moiety independently selected from the group consisting ofalkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl,alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl,cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl,cycloalkenylalkyl, heterocyclyl, and aralkyl radicals and radicalsattached to the α-carbon or α-amino acids; or

(i^(c)) a moiety independently selected from the group consisting of—OR₁₁, —NR₁₁R₁₂, —COR₁₁, —CO₂R₁₁, —CONR₁₁R₁₂, —SR₁₁, —SOR₁₁, —SO₂R₁₁,—SO₂NR₁₁R₁₂, —N(OR₁₁)(R₁₂), —P(O)(OR₁₁)(OR₁₂), —P(O)(OR₁₁)(R₁₂),—OP(O)(OR₁₁)(OR₁₂), and substituents attached to the α-carbon of α-aminoacids, wherein R₁₁ and R₁₂ are independently hydrogen or alkyl; and

(ii) optionally, one or more of R₁ or R′₁ and R₂ or R′₂, R₃ or R′₃ andR₄ or R′₄, R₅ or R′₅ and R₆ or R′₆, R₇ or R′₇, and R₈ or R′₈, R₉ or R′₉and R₁₀ or R′₁₀ together with the carbon atoms to which they areattached independently form a substituted or unsubstituted andsaturated, partially saturated, or unsaturated cycle or heterocyclehaving 3 to 20 carbon atoms; and

(iii) optionally, one or more of R₁ and R′₁, R₂ and R′₂, R₃ and R′₃, R₄and R′₄, R₅ and R′₅, R₆ and R′₆, R₇ and R′₇, R₈ and R′₈, R₉ and R′₉, andR₁₀ and R′₁₀, together with the carbon atom to which they are attachedindependently form a substituted or unsubstituted and saturated,partially saturated, or unsaturated cycle or heterocycle having 3 to 20carbon atoms; and

(iv) optionally, one or more of R₁₀ or R′₁₀ and R₁ or R′₁, R₂ or R′₂ andR₃ or R′₃, R₄ or R′₄ and R₅ or R′₅, R₆ or R′₆ and R₇ or R′₇, or R₈ orR′₈ and R₉ or R′₉ together with the carbon atoms to which they areattached independently form a substituted or unsubstituted nitrogencontaining heterocycle having 3 to 20 carbon atoms, which may be anaromatic heterocycle in which case the hydrogen attached to the nitrogenwhich is both part of the heterocycle and the macrocycle and the Rgroups attached to the carbon atoms which are both part of theheterocycle and the macrocycle are absent; and

(v) optionally, one or more of R₁, R′₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅,R′₅, R₆, R′₆, R₇, R′₇, R₈, R′₈, R₉, R′₉, R₁₀, and R′₁₀, together with adifferent one of R₁, R′₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆,R₇, R′₇, R₈, R′₈, R₉, R′₉, R₁₀, and R′₁₀, which is attached to adifferent carbon atom in the macrocyclic ligand may be bound to form astrap represented by the formula:

—(CH₂)_(I)-Q-(CH₂)_(J)—R—(CH₂)_(K)—S—(CH₂)_(L)—

wherein

I, J, K and L independently are integers from 0 to 10 and Q, R and S areindependently selected from the group consisting of alkenyl,alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl,alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl,cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, andheterocyclyl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl,sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto,ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza,silyl, siloxy, silaza, and combinations thereof; and

(vi) combinations of any of (i) through (v) above;

wherein

M is a transition metal;

X, Y and Z are independently selected from the group consisting ofhalide, oxo, aquo, hydroxo, alcohol, phenol, dioxygen, peroxo,hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino,heterocycloalkyl amino, heterocycloaryl amino, amine oxides, hydrazine,alkyl hydrazine, aryl hydrazine, nitric oxide, cyanide, cyanate,thiocyanate, isocyanate, isothiocyanate, alkyl nitrile, aryl nitrile,alkyl isonitrile, aryl isonitrile, nitrate, nitrite, azido, alkylsulfonic acid, aryl sulfonic acid, alkyl sulfoxide, aryl sulfoxide,alkyl aryl sulfoxide, alkyl sulfenic acid, aryl sulfenic acid, alkylsulfinic acid, aryl sulfinic acid, alkyl thiol carboxylic acid, arylthiol carboxylic acid, alkyl thiol thiocarboxylic acid, aryl thiolthiocarboxylic acid, alkyl carboxylic acid, aryl carboxylic acid, urea,alkyl urea, aryl urea, alkyl aryl urea, thiourea, alkyl thiourea, arylthiourea, alkyl aryl thiourea, sulfate, sulfite, bisulfate, bisulfite,thiosulfate, thiosulfite, hydrosulfite, alkyl phosphine, aryl phosphine,alkyl phosphine oxide, aryl phosphine oxide, alkyl aryl phosphine oxide,alkyl phosphine sulfide, aryl phosphine sulfide, alkyl aryl phosphinesulfide, alkyl phosphonic acid, aryl phosphonic acid, alkyl phosphinicacid, aryl phosphinic acid, alkyl phosphinous acid, aryl phosphinousacid, phosphate, thiophosphate, phosphite, pyrophosphite, triphosphate,hydrogen phosphate, dihydrogen phosphate, alkyl guanidino, arylguanidino, alkyl aryl guanidino, alkyl carbamate, aryl carbamate, alkylaryl carbamate, alkyl thiocarbamate, aryl thiocarbamate, alkylarylthiocarbamate, alkyl dithiocarbamate, aryl dithiocarbamate, alkylaryldithiocarbamate, bicarbonate, carbonate, perchlorate, chlorate,chlorite, hypochlorite, perbromate, bromate, bromite, hypobromite,tetrahalomanganate, tetrafluoroborate, hexafluoroantimonate,hypophosphite, iodate, periodate, metaborate, tetraaryl borate, tetraalkyl borate, tartrate, salicylate, succinate, citrate, ascorbate,saccharinate, amino acid, hydroxamic acid, thiotosylate, and anions ofion exchange resins, or the corresponding anions thereof; or

X, Y and Z are independently selected from the group consisting ofcharge-neutralizing anions which are derived from any monodentate orpolydentate coordinating ligand and a ligand system and thecorresponding anion thereof; or

X, Y and Z are independently attached to one or more of R₁, R′₁, R₂,R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇, R′₇, R₈, R′₈, R₉, R′₉, R₁₀,and R′₁₀; and

n is an integer from 0 to 3.

Preferably, M is selected from the group consisting of Mn²⁺, Mn³⁺, Mn⁴⁺,Mn⁶⁺, Mn⁷⁺, Fe²⁺, Fe³⁺, Fe⁴⁺, Fe⁶⁺, Ni²⁺, Ni³⁺, Cu¹⁺, Cu²⁺, V²⁺, V³⁺,V⁴⁺, and V⁵⁺.

In an alternative, the superoxide dismutase mimetic can be representedby the formula:

wherein

(i) a nitrogen of the macrocycle and two adjacent carbon atoms to whichthe nitrogen is attached independently form a substituted orunsubstituted, saturated, partially saturated or unsaturatednitrogen-containing heterocycle W having 2 to 20 carbon atoms, which maybe an aromatic heterocycle in which case the hydrogen attached to thenitrogen which is both part of the heterocycle and the macrocycle andthe R groups attached to the carbon atoms which are both part of theheterocycle and the macrocycle are absent; and

(ii) one or more of R₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇,R′₇, R₈, R′⁸, R₉, R′₉, and R₁₀ are independently:

(ii^(a)) hydrogen; or

(ii^(b)) a moiety independently selected from the group consisting ofalkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl,alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl,cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl,cycloalkenylalkyl, heterocyclyl, and aralkyl radicals and radicalsattached to the α-carbon or α-amino acids; or

(ii^(c)) a moiety independently selected from the group consisting of—OR₁₁, —NR₁₁R₁₂, —COR₁₁, —CO₂R₁₁, —CONR₁₁R₁₂, —SR₁₁, —SOR₁₁, —SO₂R₁₁,—SO₂NR₁₁R₁₂, —N(OR₁₁)(R₁₂), —P(O)(OR₁₁)(OR₁₂), —P(O)(OR₁₁)(R₁₂),—OP(O)(OR₁₁)(OR₁₂), and substituents attached to the α-carbon of α-aminoacids, wherein R₁₁ and R₁₂ are independently hydrogen or alkyl; and

(iii) optionally, one or more of R₁ and R₂ or R′₂, R₃ or R′₃ and R₄ orR′₄, R₅ or R′₅ and R₆ or R′₆, R₇ or R′₇ and R₈ or R′₈, R₉ or R′₉ and R₁₀together with the carbon atoms to which they are attached independentlyform a substituted or unsubstituted and saturated, partially saturated,or unsaturated cycle or heterocycle having 3 to 20 carbon atoms; and

(iv) optionally, one or more of R₂ and R′₂, R₃ and R′₃, R₄ and R′₄, R₅and R′₅, R₆ and R′₆, R₇ and R′₇, R₈ and R′₈, and R₉ and R′₉, togetherwith the carbon atom to which they are attached independently form asubstituted or unsubstituted and saturated, partially saturated, orunsaturated cycle or heterocycle having 3 to 20 carbon atoms; and

(v) optionally, one or more of R₂ or R′₂ and R₃ or R′₃, R₄ or R′₄ and R₅or R′₅, R₆ or R′₆ and R₇ or R′₇, or R₈ or R′₈ and R₉ or R′₉ togetherwith the carbon atoms to which they are attached independently form asubstituted or unsubstituted nitrogen containing heterocycle having 3 to20 carbon atoms, which may be an aromatic heterocycle in which case thehydrogen attached to the nitrogen which is both part of the heterocycleand the macrocycle and the R groups attached to the carbon atoms whichare both part of the heterocycle and the macrocycle are absent; and

(vi) optionally, one or more of R₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅,R₆, R′₆, R₇, R′₇, R₈, R′₈, R₉, R′₉, and R₁₀, together with a differentone of R₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇, R′₇, R₈,R′₈, R₉, R′₉, and R₁₀, which is attached to a different carbon atom inthe macrocyclic ligand may be bound to form a strap represented by theformula:

—(CH₂)_(I)-Q-(CH₂)_(J)—R—(CH₂)_(K)—S—(CH₂)_(L)—

wherein

I, J, K and L independently are integers from 0 to 10 and Q, R and S areindependently selected from the group consisting of alkenyl,alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl,alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl,cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, andheterocyclyl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl,sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto,ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza,silyl, siloxy, silaza, and combinations thereof; and

(vii) optionally, one or more of R₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅,R₆, R′₆, R₇, R′₇, R₈, R′₈, R₉, R′₉, and R₁₀, may be bound to an atom ofheterocycle W to form a strap represented by the formula:

—(CH₂)_(I)-Q-(CH₂)_(J)—R—(CH₂)_(K)—S—(CH₂)_(L)—

wherein

I, J, K and L independently are integers from 0 to 10 and Q, R and S areindependently selected from the group consisting of alkenyl,alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl,alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl,cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, andheterocyclyl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl,sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto,ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza,silyl, siloxy, silaza, and combinations thereof; and

(viii) combinations of any of (i) through (vii) above;

wherein

M is a transition metal;

X, Y and Z are independently selected from the group consisting ofhalide, oxo, aquo, hydroxo, alcohol, phenol, dioxygen, peroxo,hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino,heterocycloalkyl amino, heterocycloaryl amino, amine oxides, hydrazine,alkyl hydrazine, aryl hydrazine, nitric oxide, cyanide, cyanate,thiocyanate, isocyanate, isothiocyanate, alkyl nitrile, aryl nitrile,alkyl isonitrile, aryl isonitrile, nitrate, nitrite, azido, alkylsulfonic acid, aryl sulfonic acid, alkyl sulfoxide, aryl sulfoxide,alkyl aryl sulfoxide, alkyl sulfenic acid, aryl sulfenic acid, alkylsulfinic acid, aryl sulfinic acid, alkyl thiol carboxylic acid, arylthiol carboxylic acid, alkyl thiol thiocarboxylic acid, aryl thiolthiocarboxylic acid, alkyl carboxylic acid, aryl carboxylic acid, urea,alkyl urea, aryl urea, alkyl aryl urea, thiourea, alkyl thiourea, arylthiourea, alkyl aryl thiourea, sulfate, sulfite, bisulfate, bisulfite,thiosulfate, thiosulfite, hydrosulfite, alkyl phosphine, aryl phosphine,alkyl phosphine oxide, aryl phosphine oxide, alkyl aryl phosphine oxide,alkyl phosphine sulfide, aryl phosphine sulfide, alkyl aryl phosphinesulfide, alkyl phosphonic acid, aryl phosphonic acid, alkyl phosphinicacid, aryl phosphinic acid, alkyl phosphinous acid, aryl phosphinousacid, phosphate, thiophosphate, phosphite, pyrophosphite, triphosphate,hydrogen phosphate, dihydrogen phosphate, alkyl guanidino, arylguanidino, alkyl aryl guanidino, alkyl carbamate, aryl carbamate, alkylaryl carbamate, alkyl thiocarbamate, aryl thiocarbamate, alkylarylthiocarbamate, alkyl dithiocarbamate, aryl dithiocarbamate, alkylaryldithiocarbamate, bicarbonate, carbonate, perchlorate, chlorate,chlorite, hypochlorite, perbromate, bromate, bromite, hypobromite,tetrahalomanganate, tetrafluoroborate, hexafluoroantimonate,hypophosphite, iodate, periodate, metaborate, tetraaryl borate, tetraalkyl borate, tartrate, salicylate, succinate, citrate, ascorbate,saccharinate, amino acid, hydroxamic acid, thiotosylate, and anions ofion exchange resins, or the corresponding anions thereof; or

X, Y and Z are independently selected from the group consisting ofcharge-neutralizing anions which are derived from any monodentate orpolydentate coordinating ligand and a ligand system and thecorresponding anion thereof; or

X, Y and Z are independently attached to one or more of R₁, R₂, R′₂, R₃,R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇, R′₇, R₈, R′₈, R₉, R′₉, and R₁₀; and

n is an integer from 0 to 3.

Preferably, M is selected from the group consisting of Mn²⁺, Mn³⁺, Mn⁴⁺,Mn⁶⁺, Mn⁷⁺, Fe²⁺, Fe³⁺, Fe⁴⁺, Fe⁶⁺, Ni²⁺, Ni³⁺, Cu¹⁺, Cu²⁺, V²⁺, V³⁺,V⁴⁺, and V⁵⁺, and W is a substituted or unsubstituted pyridino moiety.

In yet another alternative, the superoxide dismutase mimetic can berepresented by the formula:

wherein

(i) a nitrogen of the macrocycle and two adjacent carbon atoms to whichthe nitrogen is attached independently form a substituted orunsubstituted, saturated, partially saturated or unsaturatednitrogen-containing heterocycle W having 2 to 20 carbon atoms, which maybe an aromatic heterocycle in which case the hydrogen attached to thenitrogen which is both part of the heterocycle and the macrocycle andthe R groups attached to the carbon atoms which are both part of theheterocycle and the macrocycle are absent; and

(ii) two sets of two adjacent carbon atoms of the macrocycleindependently form substituted or unsubstituted, saturated, partiallysaturated or unsaturated, cycles or heterocycles U and V having 3 to 20carbon atoms; and

(iii) R₁, R₂, R′₂, R₃, R₄, R₅, R′₅, R₆, R′₆, R₇, R₈, R₉, R′₉, and R₁₀are independently:

(iii^(a)) hydrogen; or

(iii^(b)) a moiety independently selected from the group consisting ofalkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl,alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl,cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl,cycloalkenylalkyl, heterocyclyl, and aralkyl radicals and radicalsattached to the α-carbon or α-amino acids; or

(iii^(c)) a moiety independently selected from the group consisting of—OR₁₁, —NR₁₁R₁₂, —COR₁₁, —CO₂R₁₁, —CONR₁₁R₁₂, —SR₁₁, —SOR₁₁, —SO₂R₁₁,—SO₂NR₁₁R₁₂, —N(OR₁₁)(R₁₂), —P(O)(OR₁₁)(OR₁₂), —P(O)(OR₁₁)(R₁₂),—OP(O)(OR₁₁)(OR₁₂), and substituents attached to the α-carbon of α-aminoacids, wherein R₁₁ and R₁₂ are independently hydrogen or alkyl; and

(iv) optionally, one or more of R₁ and R₂ or R′₂, R₅ or R′₅ and R₆ orR′₆, R₉ or R′₉ and R₁₀ together with the carbon atoms to which they areattached independently form a substituted or unsubstituted andsaturated, partially saturated, or unsaturated cycle or heterocyclehaving 3 to 20 carbon atoms; and

(v) optionally, one or more of R₂ and R′₂, R₅ and R′₅, R₆ and R′₆, andR₉ and R′₉, together with the carbon atom to which they are attachedindependently form a substituted or unsubstituted and saturated,partially saturated, or unsaturated cycle or heterocycle having 3 to 20carbon atoms; and

(vi) optionally, one or more of R₂ or R′₂ and R₃, R₄ and R₅ or R′₅, R₆or R′₆ and R₇, or R₈ and R₉ or R′₉ together with the carbon atoms towhich they are attached independently form a substituted orunsubstituted nitrogen containing heterocycle having 3 to 20 carbonatoms, which may be an aromatic heterocycle in which case the hydrogenattached to the nitrogen which is both part of the heterocycle and themacrocycle and the R groups attached to the carbon atoms which are bothpart of the heterocycle and the macrocycle are absent; and

(vii) optionally, one or more of R₁, R₂, R′₂, R₃, R₄, R₅, R′₅, R₆, R′₆,R₇, R₈, R₉, R′₉, and R₁₀, together with a different one of R₁, R₂, R′₂,R₃, R₄, R₅, R′₅, R₆, R′₆, R₇, R₈, R₉, R′₉, and R₁₀, which is attached toa different carbon atom in the macrocyclic ligand may be bound to form astrap represented by the formula:

—(CH₂)_(I)-Q-(CH₂)_(J)—R—(CH₂)_(K)—S—(CH₂)_(L)—

wherein

I, J, K and L independently are integers from 0 to 10 and Q, R and S areindependently selected from the group consisting of alkenyl,alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl,alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl,cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, andheterocyclyl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl,sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto,ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza,silyl, siloxy, silaza, and combinations thereof; and

(viii) optionally, one or more of R₁, R₂, R′₂, R₃, R₄, R₅, R′₅, R₆, R′₆,R₇, R₈, R₉, R′₉, and R₁₀, may be individually bound to an atom ofheterocycles U, V and W to form a strap represented by the formula:

—(CH₂)_(I)-Q-(CH₂)_(J)—R—(CH₂)_(K)—S—(CH₂)_(L)—

wherein

I, J, K and L independently are integers from 0 to 10 and Q, R and S areindependently selected from the group consisting of alkenyl,alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl,alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl,cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, andheterocyclyl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl,sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto,ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza,silyl, siloxy, silaza, and combinations thereof; and

(ix) combinations of any of (i) through (viii) above;

wherein

M is a transition metal;

X, Y and Z are independently selected from the group consisting ofhalide, oxo, aquo, hydroxo, alcohol, phenol, dioxygen, peroxo,hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino,heterocycloalkyl amino, heterocycloaryl amino, amine oxides, hydrazine,alkyl hydrazine, aryl hydrazine, nitric oxide, cyanide, cyanate,thiocyanate, isocyanate, isothiocyanate, alkyl nitrile, aryl nitrile,alkyl isonitrile, aryl isonitrile, nitrate, nitrite, azido, alkylsulfonic acid, aryl sulfonic acid, alkyl sulfoxide, aryl sulfoxide,alkyl aryl sulfoxide, alkyl sulfenic acid, aryl sulfenic acid, alkylsulfinic acid, aryl sulfinic acid, alkyl thiol carboxylic acid, arylthiol carboxylic acid, alkyl thiol thiocarboxylic acid, aryl thiolthiocarboxylic acid, alkyl carboxylic acid, aryl carboxylic acid, urea,alkyl urea, aryl urea, alkyl aryl urea, thiourea, alkyl thiourea, arylthiourea, alkyl aryl thiourea, sulfate, sulfite, bisulfate, bisulfite,thiosulfate, thiosulfite, hydrosulfite, alkyl phosphine, aryl phosphine,alkyl phosphine oxide, aryl phosphine oxide, alkyl aryl phosphine oxide,alkyl phosphine sulfide, aryl phosphine sulfide, alkyl aryl phosphinesulfide, alkyl phosphonic acid, aryl phosphonic acid, alkyl phosphinicacid, aryl phosphinic acid, alkyl phosphinous acid, aryl phosphinousacid, phosphate, thiophosphate, phosphite, pyrophosphite, triphosphate,hydrogen phosphate, dihydrogen phosphate, alkyl guanidino, arylguanidino, alkyl aryl guanidino, alkyl carbamate, aryl carbamate, alkylaryl carbamate, alkyl thiocarbamate, aryl thiocarbamate, alkylarylthiocarbamate, alkyl dithiocarbamate, aryl dithiocarbamate, alkylaryldithiocarbamate, bicarbonate, carbonate, perchlorate, chlorate,chlorite, hypochlorite, perbromate, bromate, bromite, hypobromite,tetrahalomanganate, tetrafluoroborate, hexafluoroantimonate,hypophosphite, iodate, periodate, metaborate, tetraaryl borate, tetraalkyl borate, tartrate, salicylate, succinate, citrate, ascorbate,saccharinate, amino acid, hydroxamic acid, thiotosylate, and anions ofion exchange resins, or the corresponding anions thereof; or

X, Y and Z are independently selected from the group consisting ofcharge-neutralizing anions which are derived from any monodentate orpolydentate coordinating ligand and a ligand system and thecorresponding anion thereof; or

X, Y and Z are independently attached to one or more of R₁, R₂, R′₂, R₃,R₄, R₅, R′₅, R₆, R′₆, R₇, R₈, R₉, R′₉, and R₁₀; and

n is an integer from 0 to 3.

Preferably, M is selected from the group consisting of Mn²⁺, Mn³⁺, Mn⁴⁺,Mn⁶⁺, Mn⁷⁺, Fe²⁺, Fe³⁺, Fe⁴⁺, Fe⁶⁺, Ni²⁺, Ni³⁺, Cu¹⁺, Cu²⁺, V²⁺, V³⁺,V⁴⁺, and V⁵⁺. In accordance with a further aspect of the invention, Uand V are saturated cycloalkyl heterocycles having 3 to 20 carbon atomspreferably saturated cycloalkyl heterocycles having 4 to 10 carbonatoms, and still more preferably U and V are trans-cyclohexanyl fusedrings. In yet another aspect of the present invention, W is asubstituted or unsubstituted pyridino moiety, more preferably, U and Vare trans-cyclohexanyl fused rings and W is a substituted pyridinomoiety. Preferably, the superoxide dismutase mimetic can be representedby the formula:

The ROS scavenger can be administered in an amount of at most 0.015mg/kg, or preferably at most 2 mg/kg. In yet another aspect, thepharmaceutically acceptable formulation is a pharmaceutically acceptableoral formulation and administering comprises administering orally.Preferably, the patient is a human patient and the oral mucositis is aresult of chemotherapy or radiation therapy.

Another aspect of the invention can be a method of treating a cancer,the method comprising: a) administering to a subject in need of cancertreatment a pharmaceutical composition comprising a superoxide dismutasemimetic; and b) administering to the subject an effective amount of acancer treatment, whereby the superoxide dismutase mimetic prevents orreduces oral mucositis in the subject. The cancer treatment can becomprised of radiation therapy and chemotherapy. In said method oftreating a cancer, the superoxide dismutase mimetic can be a reactiveoxygen species scavenger, and the pharmaceutical composition can furthercomprise at least one additional reactive oxygen species scavengerselected from the group consisting of amifostine and N-acetylcysteine.Additionally, the method of treating a cancer can further compriseadministering a pharmaceutical composition which upregulates expressionof at least one transcription factor which increases expression of oneor more genes controlling at least one naturally occurring antioxidantpathway. The composition which upregulates expression of at least onetranscription factor can be palifermin, and the transcription factorupregulated can be Nrf-2.

In yet another aspect of the present invention, a kit can be providedfor treating oral mucositis, the kit comprising: (a) a ROS scavenger,wherein the ROS scavenger can be a superoxide dismutase; (b) oneadditional pharmaceutical compound selected from the group consisting ofa chemotherapeutic agent; (c) a non-superoxide dismustase mimeticradical scavenger; and (d) instructions for administering the superoxidedismutase to a subject in need of cancer therapy. A chemotherapeuticagent can be selected from a group consisting of all-trans retinoicacid, azacitidine, azathioprine, bleomycin, carboplatin, capecitabine,cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin,docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone,etoposide, fluorouracil, gemcitabine, hydroxyurea, idarubicin, imatinib,mechlorethamine, mercaptopurine, methotrexate, mitoxantrone,oxaliplatin, paclitaxel, pemetrexed, teniposide, tiguanine, valrubicin,vinblastine, vincristine, vindesine, vinorelbine. A non-superoxidedismutase mimetic radical scavenger can be selected from the group ofamifostine and N-acetylcysteine. A superoxide dismutase mimetic can beM40403.

These and other features, aspects and advantages of the presentinvention will become better understood with reference to the followingdescription, examples and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a timeline of a study for treatment groups 1-6 to evaluate theeffect of M40403, administered by either ip or topical routes. The gradeof mucositis was scored, beginning on day 6, and for every second daythereafter, through and including day 28.

FIG. 2 is a validated photographic scale for mucositis scoring.

FIG. 3 illustrates the percent daily weight change for the groupstreated with intraperitoneal (ip) injection of M40403 (i.e. groups 1, 2,3, and 6), including the control group, and for the groups treatedtopically with M40403 (i.e. groups 4 and 5).

FIG. 4 illustrates the mean percent weight gain for the groups treatedip with M40403 (i.e. groups 1, 2, 3, and 6), including the controlgroup, and for the groups treated topically with M40403 (i.e. groups 4and 5).

FIG. 5 illustrates the mean daily mucositis scores the groups treated ipwith M40403 (i.e. groups 1, 2, 3, and 6), including the control group,and for the groups treated topically with M40403 (i.e. groups 4 and 5).

FIG. 6 illustrates the percentage of animal days with a mucositis scoreof 3 or higher for groups treated ip with M40403 (i.e. groups 1, 2, 3,and 6), including the control group, and for the groups treatedtopically with M40403 (i.e. groups 4 and 5).

FIG. 7 is a timeline of a study for treatment groups 1-9 to evaluate theeffect of M40403, administered by either ip or topical routes. The gradeof mucositis was scored, beginning on day 6, and for every second daythereafter, through and including day 28.

FIG. 8 is a validated photographic scale for mucositis scoring.

FIG. 9 illustrates the percent daily weight change for the groupstreated ip with M40403 (i.e. groups 2-9) and for the control group (i.e.group 1).

FIG. 10 illustrates the mean percent weight gain for the groups treatedip with M40403 (i.e. groups 2-9) and for the control group (i.e. group1).

FIG. 11 illustrates the mean daily mucositis scores the groups treatedip with M40403 (i.e. groups 2-9) and for the control group (i.e. group1).

FIG. 12 illustrates the percentage of animal days with a mucositis scoreof 3 or higher for groups treated ip with M40403 (i.e. groups 2-9) andfor the control group (i.e. group 1).

DETAILED DESCRIPTION OF THE INVENTION Abbreviations and Definitions

To facilitate understanding of the invention, a number of terms andabbreviations as used herein are defined below as follows:

The term “alkenyl”, alone or in combination, means an alkyl substituenthaving one or more double bonds. Examples of such alkenyl substituentsinclude, but are not limited to, ethenyl, propenyl, 1-butenyl,cis-2-butenyl, trans-2-butenyl, iso-butylenyl, cis-2-pentenyl,trans-2-pentenyl, 3-methyl-1-butenyl, 2,3-dimethyl-2-butenyl,1-pentenyl, 1-hexenyl, 1-octenyl, decenyl, dodecenyl, tetradecenyl,hexadecenyl, cis- and trans-9-octadecenyl, 1,3-pentadienyl,2,4-pentadienyl, 2,3-pentadienyl, 1,3-hexadienyl, 2,4-hexadienyl,5,8,11,14-eicosatetraenyl, and 9,12,15-octadecatrienyl.

The term “alkyl”, alone or in combination, means a straight-chain orbranched-chain alkyl substituent containing from 1 to about 22 carbonatoms, preferably from about 1 to about 18 carbon atoms, and mostpreferably from about 1 to about 12 carbon atoms. Examples of suchsubstituents include, but are not limited to, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,hexyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyland eicosyl.

The terms “alkylcycloalkyl” and “alkenylcycloalkyl” mean a cycloalkylsubstituent as defined above which is substituted by an alkyl or alkenylsubstituent as defined above. Examples of alkylcycloalkyl andalkenylcycloalkyl substituents include, but are not limited to,2-ethylcyclobutyl, 1-methylcyclopentyl, 1-hexylcyclopentyl,1-methylcyclohexyl, 1-(9-octadecenyl)cyclopentyl and1-(9-octadecenyl)cyclohexyl.

The terms “alkylcycloalkenyl” and “alkenylcycloalkenyl” means acycloalkenyl substituent as defined above which is substituted by analkyl or alkenyl substituent as defined above. Examples ofalkylcycloalkenyl and alkenylcycloalkenyl substituents include, but arenot limited to, 1-methyl-2-cyclopentyl, 1-hexyl-2-cyclopentenyl,1-ethyl-2-cyclohexenyl, 1-butyl-2-cyclohexenyl,1-(9-octadecenyl)-2-cyclohexenyl and 1-(2-pentenyl)-2-cyclohexenyl.

The term “alkynyl”, alone or in combination, means an alkyl substituenthaving one or more triple bonds. Examples of such alkynyl groupsinclude, but are not limited to, ethynyl, propynyl (propargyl),1-butynyl, 1-octynyl, 9-octadecynyl, 1,3-pentadiynyl, 2,4-pentadiynyl,1,3-hexadiynyl, and 2,4-hexadiynyl.

The term “aralkyl”, alone or in combination, means an alkyl orcycloalkyl substituent as defined above in which one hydrogen atom isreplaced by an aryl substituent as defined above, such as benzyl,2-phenylethyl, and the like.

The term “aryl”, alone or in combination, means a phenyl or naphthylsubstituent which optionally carries one or more substituents selectedfrom alkyl, cycloalkyl, cycloalkenyl, aryl, heterocycle, alkoxyaryl,alkaryl, alkoxy, halogen, hydroxy, amine, cyano, nitro, alkylthio,phenoxy, ether, trifluoromethyl and the like, such as phenyl, p-tolyl,4-methoxyphenyl, 4-(tert-butoxy)phenyl, 4-fluorophenyl, 4-chlorophenyl,4-hydroxyphenyl, 1-naphthyl, 2-naphthyl, and the like.

The term “cycloalkenyl”, alone or in combination, means a cycloalkylsubstituent having one or more double bonds. Examples of cycloalkenylsubstituents include, but are not limited to, cyclopentenyl,cyclohexenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl andcyclooctadienyl.

The terms “cyclic”, “cycle” or “cycylyl” means a ring structurecontaining 3 to 20 carbon atoms, preferably 5 to 10 carbon atoms, whichmay be heterocyclic. The cyclic, cycle or cycylyl can also contain morethan one ring.

The term “cycloalkenylalkyl” means an alkyl substituent as defined abovewhich is substituted by a cycloalkenyl substituent as defined above.Examples of cycloalkenylalkyl substituents include, but are not limitedto, 2-cyclohexen-1-ylmethyl, 1-cyclopenten-1-ylmethyl,2-(1-cyclohexen-1-yl)ethyl, 3-(1-cyclopenten-1-yl)propyl,1-(1-cyclohexen-1-ylmethyl)pentyl, 1-(1-cyclopenten-1-yl)hexyl,6-(1-cyclohexen-1-1-yl)hexyl, 1-(1-cyclopenten-1-yl)nonyl and1-(1-cyclohexen-1-yl)nonyl.

The term “cycloalkyl”, alone or in combination means a cycloalkylradical containing from 3 to about 10, preferably from 3 to about 8, andmost preferably from 3 to about 6, carbon atoms. Examples of suchcycloalkyl substituents include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, andperhydronaphthyl.

The term “cycloalkylalkyl” means an alkyl substituent as defined abovewhich is substituted by a cycloalkyl substituent as defined above.Examples of cycloalkylalkyl substituents include, but are not limitedto, cyclohexylmrthyl, cyclopentylmethyl, (4-isopropylcyclohexyl)methyl,(4-t-butyl-cyclohexyl)methyl, 3-cyclohexylpropyl,2-cyclohexylmethylpentyl, 3-cyclopentylmethylhexyl,1-(4-neopentylcyclohexyl)methylhexyl, and1-(4-isopropylcyclohexyl)methylheptyl.

The term “cycloalkylcycloalkyl” means a cycloalkyl substituent asdefined above which is substituted by another cycloalkyl substituent asdefined above. Examples of cycloalkylcycloalkyl substituents include,but are not limited to, cyclohexylcyclopentyl and cyclohexylcyclohexyl.

The term “halide” means chloride, fluoride, iodide, or bromide.

The term “heterocyclic”, “heterocycle” or “heterocycylyl” means acyclic, cycle or cycylyl containing at least one other kind of atom, inaddition to carbon, in the ring. Such atoms include, but are not limitedto, nitrogen, oxygen and sulfur. The heterocyclic can also contain morethan one ring. Examples of heterocyclics include, but are not limitedto, pyrrolidinyl, piperidyl, imidazolidinyl, tetrahydrofuryl,tetrahydrothienyl, furyl, thienyl, pyridyl, quinolyl, isoquinolyl,pyridazinyl, pyrazinyl, indolyl, imidazolyl, oxazolyl, thiazolyl,pyrazolyl, pyridinyl, benzoxadiazolyl, benzothiadiazolyl, triazolyl andtetrazolyl groups.

The term “nitrogen containing heterocycle” means a ring structure inwhich 2 carbons and a nitrogen of the ring are shared with thefifteen-membered macrocyclic ligand. The nitrogen containing heterocyclecan contain 2 to 20, preferably 4 to 10, carbon atoms, can besubstituted or unsubstituted, saturated, partially saturated orunsaturated, and can also contain nitrogen, oxygen and/or sulfur atomsin the portion of the ring which is not also part of thefifteen-membered macrocyclic ligand.

The term “oral mucositis” shall also include stomatitis, smallintestine-titis, large intestine-titis, proctitis, and similarconditions affecting the mucosal lining of the entire gastrointestinaltract, and related conditions.

The term “R groups” means the group of variable substituents designatedas “R” attached to the carbon atoms of the macrocycle, i.e., R₁, R′₁,R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇, R′₇, R₈, R′₈, R₉, R′₉,R₁₀, and R′₁₀.

The term “saturated, partially saturated or unsaturated cycle orheterocycle” means a fused ring structure in which 2 carbons of the ringare also part of the fifteen-membered macrocyclic ligand in which thering can contain no double bonds (in the case of a saturated ringstructure) or at least one double bond, which may be conjugated orunconjugated with another double bond. The ring structure can contain 3to 20 carbon atoms, preferably 5 to 10 carbon atoms, which may beheterocyclic. The cyclic can also contain more than one ring.

In addition, the following abbreviations have the following meanings:

AUC Area under the curve bid Twice daily FGF Fibroblast growth factor g,mg, ml, kg Gram, milligram, milliliter, kilogram Gy Gray ipIntraperitoneal ma Milliamp mM Millimolar mm, cm Millimeter, centimeterSEM Standard error of the mean top Topical

Methods for Treating Oral Mucositis

The present invention involves the administration of a ROS scavenger inthe treatment of oral mucositis. A ROS scavenger of the presentinvention is a superoxide dismutase mimetic, a non-proteinaceousmolecule that catalyzes the conversion the of the superoxide radical,02′, to molecular oxygen and hydrogen peroxide. Such a molecule can,like a native superoxide dismutase enzyme, reduce cell injury resultingfrom superoxide radical found in diseases involving oxidative stresssuch as inflammation (Salvemini et al, Arthritis & Rheumatism44:2909-2921, 2001). The ROS scavengers of the present invention can bepentaaza-macrocyclic complexes, and more specifically, thosecompositions as disclosed in U.S. Pat. Nos. 5,610,293, 5,637,578,5,874,421, 5,976,498, 6,084,093, 6,180,620, 6,204,259, 6,214,817,6,245,758, 6,395,725, and 6,525,041, each of which is incorporatedherein by reference in its entirety.

The superoxide dismutase mimetics of the present invention can berepresented by the following formula:

wherein

(i) R₁, R′₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇, R′₇, R₈,R′₈, R₉, R′₉, R₁₀, and R′₁₀ are independently:

(i^(a)) hydrogen; or

(i^(b)) a moiety independently selected from the group consisting ofalkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl,alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl,cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl,cycloalkenylalkyl, and aralkyl radicals and radicals attached to theα-carbon or α-amino acids heterocyclyl; or

(i^(c)) a moiety independently selected from the group consisting of—OR₁₁, —NR₁₁R₁₂, —COR₁₁, —CO₂R₁₁, —CONR₁₁R₁₂, —SR₁₁, —SOR₁₁, —SO₂R₁₁,—SO₂NR₁₁R₁₂, —N(OR₁₁)(R₁₂), —P(O)(OR₁₁)(OR₁₂), —P(O)(OR₁₁)(R₁₂),—OP(O)(OR₁₁)(OR₁₂), and substituents attached to the α-carbon of α-aminoacids, wherein R₁₁ and R₁₂ are independently hydrogen or alkyl; and

(ii) optionally, one or more of R₁ or R′₁ and R₂ or R′₂, R₃ or R′₃ andR₄ or R′₄, R₅ or R′₅ and R₆ or R′₆, R₇ or R′₇ and R₈ or R′₈, R₉ or R′₉and R₁₀ or R′₁₀ together with the carbon atoms to which they areattached independently form a substituted or unsubstituted andsaturated, partially saturated, or unsaturated cycle or heterocyclehaving 3 to 20 carbon atoms; and

(iii) optionally, one or more of R₁ and R′₁, R₂ and R′₂, R₃ and R′₃, R₄and R′₄, R₅ and R′₅, R₆ and R′₆, R₇ and R′₇, R₈ and R′₈, R₉ and R′₉, andR₁₀ and R′₁₀, together with the carbon atom to which they are attachedindependently form a substituted or unsubstituted and saturated,partially saturated, or unsaturated cycle or heterocycle having 3 to 20carbon atoms; and

(iv) optionally, one or more of R₁₀ or R′₁₀ and R₁ or R′₁, R₂ or R′₂ andR₃ or R′₃, R₄ or R′₄ and R₅ or R′₅, R₆ or R′₆ and R₇ or R′₇, or R₈ orR′₈ and R₉ or R′₉ together with the carbon atoms to which they areattached independently form a substituted or unsubstituted nitrogencontaining heterocycle having 3 to 20 carbon atoms, which may be anaromatic heterocycle in which case the hydrogen attached to the nitrogenwhich is both part of the heterocycle and the macrocycle and the Rgroups attached to the carbon atoms which are both part of theheterocycle and the macrocycle are absent; and

(v) optionally, one or more of R₁, R′₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅,R′₅, R₆, R′₆, R₇, R′₇, R₈, R′₈, R₉, R′₉, R₁₀, and R′₁₀, together with adifferent one of R₁, R′₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆,R₇, R′₇, R₈, R′_(B), R₉, R′₉, R₁₀, and R′₁₀, which is attached to adifferent carbon atom in the macrocyclic ligand may be bound to form astrap represented by the formula:

—(CH₂)_(I)-Q-(CH₂)_(J)—R—(CH₂)_(K)—S—(CH₂)_(L)—

wherein

I, J, K and L independently are integers from 0 to 10 and Q, R and S areindependently selected from the group consisting of alkenyl,alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl,alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl,cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, andheterocyclyl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl,sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto,ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza,silyl, siloxy, silaza, and combinations thereof; and

(vi) combinations of any of (i) through (v) above.

Thus, the pentaaza-macrocyclic ligand compositions useful in the presentinvention can have any combinations of substituted or unsubstituted Rgroups, saturated, partially saturated or unsaturated cyclics,heterocyclics, nitrogen containing heterocycles, or straps as definedabove.

M can be a transition metal, preferably Mn²⁺, Mn³⁺, Mn⁴⁺, Mn⁶⁺, Mn⁷⁺,Fe²⁺, Fe³⁺, Fe⁴⁺, Fe⁶⁺, Ni²⁺, Ni³⁺, Cu¹⁺, Cu²⁺, V²⁺, V³⁺, V⁴⁺, or V⁵⁺.X, Y and Z can independently be selected from the group consisting ofhalide, oxo, aquo, hydroxo, alcohol, phenol, dioxygen, peroxo,hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino,heterocycloalkyl amino, heterocycloaryl amino, amine oxides, hydrazine,alkyl hydrazine, aryl hydrazine, nitric oxide, cyanide, cyanate,thiocyanate, isocyanate, isothiocyanate, alkyl nitrile, aryl nitrile,alkyl isonitrile, aryl isonitrile, nitrate, nitrite, azido, alkylsulfonic acid, aryl sulfonic acid, alkyl sulfoxide, aryl sulfoxide,alkyl aryl sulfoxide, alkyl sulfenic acid, aryl sulfenic acid, alkylsulfinic acid, aryl sulfinic acid, alkyl thiol carboxylic acid, arylthiol carboxylic acid, alkyl thiol thiocarboxylic acid, aryl thiolthiocarboxylic acid, alkyl carboxylic acid, aryl carboxylic acid, urea,alkyl urea, aryl urea, alkyl aryl urea, thiourea, alkyl thiourea, arylthiourea, alkyl aryl thiourea, sulfate, sulfite, bisulfate, bisulfite,thiosulfate, thiosulfite, hydrosulfite, alkyl phosphine, aryl phosphine,alkyl phosphine oxide, aryl phosphine oxide, alkyl aryl phosphine oxide,alkyl phosphine sulfide, aryl phosphine sulfide, alkyl aryl phosphinesulfide, alkyl phosphonic acid, aryl phosphonic acid, alkyl phosphinicacid, aryl phosphinic acid, alkyl phosphinous acid, aryl phosphinousacid, phosphate, thiophosphate, phosphite, pyrophosphite, triphosphate,hydrogen phosphate, dihydrogen phosphate, alkyl guanidino, arylguanidino, alkyl aryl guanidino, alkyl carbamate, aryl carbamate, alkylaryl carbamate, alkyl thiocarbamate, aryl thiocarbamate, alkylarylthiocarbamate, alkyl dithiocarbamate, aryl dithiocarbamate, alkylaryldithiocarbamate, bicarbonate, carbonate, perchlorate, chlorate,chlorite, hypochlorite, perbromate, bromate, bromite, hypobromite,tetrahalomanganate, tetrafluoroborate, hexafluoroantimonate,hypophosphite, iodate, periodate, metaborate, tetraaryl borate, tetraalkyl borate, tartrate, salicylate, succinate, citrate, ascorbate,saccharinate, amino acid, hydroxamic acid, thiotosylate, and anions ofion exchange resins, or the corresponding anions thereof; or

X, Y and Z are independently selected from the group consisting ofcharge-neutralizing anions which are derived from any monodentate orpolydentate coordinating ligand and a ligand system and thecorresponding anion thereof; or

X, Y and Z are independently attached to one or more of R₁, R′₁, R₂,R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇, R′₇, R₈, R′₈, R₉, R′₉, R₁₀,and R′₁₀. n is preferably an integer from 0 to 3.

Alternatively, the superoxide dismutase mimetic can be represented bythe formula:

wherein

(i) a nitrogen of the macrocycle and two adjacent carbon atoms to whichthe nitrogen is attached independently form a substituted orunsubstituted, saturated, partially saturated or unsaturatednitrogen-containing heterocycle W having 2 to 20 carbon atoms, which maybe an aromatic heterocycle in which case the hydrogen attached to thenitrogen which is both part of the heterocycle and the macrocycle andthe R groups attached to the carbon atoms which are both part of theheterocycle and the macrocycle are absent; and

(ii) one or more of R₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇,R′₇, R₈, R′₈, R₉, R′₉, and R₁₀ are independently:

(ii^(a)) hydrogen; or

(ii^(b)) a moiety independently selected from the group consisting ofalkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl,alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl,cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl,cycloalkenylalkyl, heterocyclyl, and aralkyl radicals and radicalsattached to the α-carbon or α-amino acids; or

(ii^(c)) a moiety independently selected from the group consisting of—OR₁, —NR₁₁R₁₂, —COR₁₁, —CO₂R₁₁, —CONR₁₁R₁₂, —SR₁₁, —SOR₁₁, —SO₂R₁₁,—SO₂NR₁₁R₁₂, —N(OR₁₁)(R₁₂), —P(O)(OR₁₁)(OR₁₂), —P(O)(OR₁₁)(R₁₂),—OP(O)(OR₁₁)(OR₁₂), and substituents attached to the α-carbon of α-aminoacids, wherein R₁₁ and R₁₂ are independently hydrogen or alkyl; and

(iii) optionally, one or more of R₁ and R₂ or R′₂, R₃ or R′₃ and R₄ orR′₄, R₅ or R′₅ and R₆ or R′₆, R₇ or R′₇, and R₈ or R′₈, R₉ or R′₉ andR₁₀ together with the carbon atoms to which they are attachedindependently form a substituted or unsubstituted and saturated,partially saturated, or unsaturated cycle or heterocycle having 3 to 20carbon atoms; and

(iv) optionally, one or more of R₂ and R′₂, R₃ and R′₃, R₄ and R′₄, R₅and R′₅, R₆ and R′₆, R₇ and R′₇, R₈ and R′₈, and R₉ and R′₉, togetherwith the carbon atom to which they are attached independently form asubstituted or unsubstituted and saturated, partially saturated, orunsaturated cycle or heterocycle having 3 to 20 carbon atoms; and

(v) optionally, one or more of R₂ or R′₂ and R₃ or R′₃, R₄ or R′₄ and R₅or R′₅, R₆ or R′₆ and R₇ or R′₇, or R₈ or R′₈ and R₉ or R′₉ togetherwith the carbon atoms to which they are attached independently form asubstituted or unsubstituted nitrogen containing heterocycle having 3 to20 carbon atoms, which may be an aromatic heterocycle in which case thehydrogen attached to the nitrogen which is both part of the heterocycleand the macrocycle and the R groups attached to the carbon atoms whichare both part of the heterocycle and the macrocycle are absent; and

(vi) optionally, one or more of R₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅,R₆, R′₆, R₇, R′₇, R₈, R′₈, R₉, R′₉, and R₁₀, together with a differentone of R₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇, R′₇, R₈,R′₈, R₉, R′₉, and R₁₀, which is attached to a different carbon atom inthe macrocyclic ligand may be bound to form a strap represented by theformula:

—(CH₂)_(I)-Q-(CH₂)_(J)—R—(CH₂)_(K)—S—(CH₂)_(L)—

wherein

I, J, K and L independently are integers from 0 to 10 and Q, R and S areindependently selected from the group consisting of alkenyl,alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl,alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl,cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, andheterocyclyl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl,sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto,ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza,silyl, siloxy, silaza, and combinations thereof; and

(vii) optionally, one or more of R₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅,R₆, R′₆, R₇, R′₇, R₈, R′₈, R₉, R′₉, and R₁₀, may be bound to an atom ofheterocycle W to form a strap represented by the formula:

—(CH₂)_(I)-Q-(CH₂)_(J)—R—(CH₂)_(K)—S—(CH₂)_(L)—

wherein

I, J, K and L independently are integers from 0 to 10 and Q, R and S areindependently selected from the group consisting of alkenyl,alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl,alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl,cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, andheterocyclyl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl,sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto,ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza,silyl, siloxy, silaza, and combinations thereof; and

(viii) combinations of any of (i) through (vii) above.

Thus, the pentaaza-macrocyclic ligand compositions useful in the presentinvention can have any combinations of substituted or unsubstituted Rgroups, saturated, partially saturated or unsaturated cyclics,heterocyclics, nitrogen containing heterocycles, or straps as definedabove, which may or may not independently connect the W loop and thepentaaza macrocycle.

M can be a transition metal, preferably Mn²⁺, Mn³⁺, Mn⁴⁺, Mn⁶⁺, Mn⁷⁺,Fe²⁺, Fe³⁺, Fe⁴⁺, Fe⁶⁺, Ni²⁺, Ni³⁺, Cu¹⁺, Cu²⁺, V²⁺, V³⁺, V⁴⁺, or V⁵⁺.X, Y and Z can independently be selected from the group consisting ofhalide, oxo, aquo, hydroxo, alcohol, phenol, dioxygen, peroxo,hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino,heterocycloalkyl amino, heterocycloaryl amino, amine oxides, hydrazine,alkyl hydrazine, aryl hydrazine, nitric oxide, cyanide, cyanate,thiocyanate, isocyanate, isothiocyanate, alkyl nitrile, aryl nitrile,alkyl isonitrile, aryl isonitrile, nitrate, nitrite, azido, alkylsulfonic acid, aryl sulfonic acid, alkyl sulfoxide, aryl sulfoxide,alkyl aryl sulfoxide, alkyl sulfenic acid, aryl sulfenic acid, alkylsulfinic acid, aryl sulfinic acid, alkyl thiol carboxylic acid, arylthiol carboxylic acid, alkyl thiol thiocarboxylic acid, aryl thiolthiocarboxylic acid, alkyl carboxylic acid, aryl carboxylic acid, urea,alkyl urea, aryl urea, alkyl aryl urea, thiourea, alkyl thiourea, arylthiourea, alkyl aryl thiourea, sulfate, sulfite, bisulfate, bisulfite,thiosulfate, thiosulfite, hydrosulfite, alkyl phosphine, aryl phosphine,alkyl phosphine oxide, aryl phosphine oxide, alkyl aryl phosphine oxide,alkyl phosphine sulfide, aryl phosphine sulfide, alkyl aryl phosphinesulfide, alkyl phosphonic acid, aryl phosphonic acid, alkyl phosphinicacid, aryl phosphinic acid, alkyl phosphinous acid, aryl phosphinousacid, phosphate, thiophosphate, phosphite, pyrophosphite, triphosphate,hydrogen phosphate, dihydrogen phosphate, alkyl guanidino, arylguanidino, alkyl aryl guanidino, alkyl carbamate, aryl carbamate, alkylaryl carbamate, alkyl thiocarbamate, aryl thiocarbamate, alkylarylthiocarbamate, alkyl dithiocarbamate, aryl dithiocarbamate, alkylaryldithiocarbamate, bicarbonate, carbonate, perchlorate, chlorate,chlorite, hypochlorite, perbromate, bromate, bromite, hypobromite,tetrahalomanganate, tetrafluoroborate, hexafluoroantimonate,hypophosphite, iodate, periodate, metaborate, tetraaryl borate, tetraalkyl borate, tartrate, salicylate, succinate, citrate, ascorbate,saccharinate, amino acid, hydroxamic acid, thiotosylate, and anions ofion exchange resins, or the corresponding anions thereof. n ispreferably an integer from 0 to 3. W can be a substituted orunsubstituted pyridino moiety.

In another alternative, the superoxide dismutase mimetic can berepresented by the formula:

wherein

(i) a nitrogen of the macrocycle and two adjacent carbon atoms to whichthe nitrogen is attached independently form a substituted orunsubstituted, saturated, partially saturated or unsaturatednitrogen-containing heterocycle W having 2 to 20 carbon atoms, which maybe an aromatic heterocycle in which case the hydrogen attached to thenitrogen which is both part of the heterocycle and the macrocycle andthe R groups attached to the carbon atoms which are both part of theheterocycle and the macrocycle are absent; and

(ii) two sets of two adjacent carbon atoms of the macrocycleindependently form substituted or unsubstituted, saturated, partiallysaturated or unsaturated, cycles or heterocycles U and V having 3 to 20carbon atoms; and

(iii) R₁, R₂, R′₂, R₃, R₄, R₅, R′₅, R₆, R′₆, R₇, R₈, R₉, R′₉, and R₁₀are independently:

(iii^(a)) hydrogen; or

(iii^(b)) a moiety independently selected from the group consisting ofalkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl,alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl,cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl,cycloalkenylalkyl, heterocyclyl, and aralkyl radicals and radicalsattached to the α-carbon or α-amino acids; or

(iii^(c)) a moiety independently selected from the group consisting of—OR₁₁, —NR₁₁R₁₂, —COR₁₁, —CO₂R₁₁, —CONR₁₁R₁₂, —SR₁₁, —SOR₁₁, —SO₂R₁₁,—SO₂NR₁₁R₁₂, —N(OR₁₁)(R₁₂), —P(O)(OR₁₁)(OR₁₂), —P(O)(OR₁₁)(R₁₂),—OP(O)(OR₁₁)(OR₁₂), and substituents attached to the α-carbon of α-aminoacids, wherein R₁₁ and R₁₂ are independently hydrogen or alkyl; and

(iv) optionally, one or more of R₁ and R₂ or R′₂, R₅ or R′₅ and R₆ orR′₆, R₉ or R′₉ and R₁₀ together with the carbon atoms to which they areattached independently form a substituted or unsubstituted andsaturated, partially saturated, or unsaturated cycle or heterocyclehaving 3 to 20 carbon atoms; and

(v) optionally, one or more of R₂ and R′₂, R₅ and R′₅, R₆ and R′₆, andR₉ and R′₉, together with the carbon atom to which they are attachedindependently form a substituted or unsubstituted and saturated,partially saturated, or unsaturated cycle or heterocycle having 3 to 20carbon atoms; and

(vi) optionally, one or more of R₂ or R′₂ and R₃, R₄ and R₅ or R′₅, R₆or R′₆ and R₇, or R₈ and R₉ or R′₉ together with the carbon atoms towhich they are attached independently form a substituted orunsubstituted nitrogen containing heterocycle having 3 to 20 carbonatoms, which may be an aromatic heterocycle in which case the hydrogenattached to the nitrogen which is both part of the heterocycle and themacrocycle and the R groups attached to the carbon atoms which are bothpart of the heterocycle and the macrocycle are absent; and

(vii) optionally, one or more of R₁, R₂, R′₂, R₃, R₄, R₅, R′₅, R₆, R′₆,R₇, R₈, R₉, R′₉, and R₁₀, together with a different one of R₁, R₂, R′₂,R₃, R₄, R₅, R′₅, R₆, R′₆, R₇, R₈, R₉, R′₉, and R₁₀, which is attached toa different carbon atom in the macrocyclic ligand may be bound to form astrap represented by the formula:

—(CH₂)_(I)-Q-(CH₂)_(J)—R—(CH₂)_(K)—S—(CH₂)_(L)—

wherein

I, J, K and L independently are integers from 0 to 10 and Q, R and S areindependently selected from the group consisting of alkenyl,alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl,alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl,cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, andheterocyclyl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl,sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto,ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza,silyl, siloxy, silaza, and combinations thereof; and

(viii) optionally, one or more of R₁, R₂, R′₂, R₃, R₄, R₅, R′₅, R₆, R′₆,R₇, R₈, R₉, R′₉, and R₁₀, may be individually bound to an atom ofheterocycles U, V and W to form a strap represented by the formula:

—(CH₂)_(I)-Q-(CH₂)_(J)—R—(CH₂)_(K)—S—(CH₂)_(L)—

wherein

I, J, K and L independently are integers from 0 to 10 and Q, R and S areindependently selected from the group consisting of alkenyl,alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl,alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl,cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, andheterocyclyl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl,sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto,ester, alcohol, carbamate, urea, thiocarbonyl, borates, boranes, boraza,silyl, siloxy, silaza, and combinations thereof; and

(ix) combinations of any of (i) through (viii) above;

Thus, the pentaaza-macrocyclic ligand compositions useful in the presentinvention can have any combinations of substituted or unsubstituted Rgroups, saturated, partially saturated or unsaturated cyclics,heterocyclics, nitrogen containing heterocycles, or straps as definedabove, which may or may not independently connect the W, U or V loopsand the pentaaza macrocycle.

M can be a transition metal, preferably Mn²⁺, Mn³⁺, Mn⁴⁺, Mn⁶⁺, Mn⁷⁺,Fe²⁺, Fe³⁺, Fe⁴⁺, Fe⁶⁺, Ni²⁺, Ni³⁺, Cu¹⁺, Cu²⁺, V²⁺, V³⁺, V⁴⁺, or V⁵⁺.X, Y and Z can independently be selected from the group consisting ofhalide, oxo, aquo, hydroxo, alcohol, phenol, dioxygen, peroxo,hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino,heterocycloalkyl amino, heterocycloaryl amino, amine oxides, hydrazine,alkyl hydrazine, aryl hydrazine, nitric oxide, cyanide, cyanate,thiocyanate, isocyanate, isothiocyanate, alkyl nitrile, aryl nitrile,alkyl isonitrile, aryl isonitrile, nitrate, nitrite, azido, alkylsulfonic acid, aryl sulfonic acid, alkyl sulfoxide, aryl sulfoxide,alkyl aryl sulfoxide, alkyl sulfenic acid, aryl sulfenic acid, alkylsulfinic acid, aryl sulfinic acid, alkyl thiol carboxylic acid, arylthiol carboxylic acid, alkyl thiol thiocarboxylic acid, aryl thiolthiocarboxylic acid, alkyl carboxylic acid, aryl carboxylic acid, urea,alkyl urea, aryl urea, alkyl aryl urea, thiourea, alkyl thiourea, arylthiourea, alkyl aryl thiourea, sulfate, sulfite, bisulfate, bisulfite,thiosulfate, thiosulfite, hydrosulfite, alkyl phosphine, aryl phosphine,alkyl phosphine oxide, aryl phosphine oxide, alkyl aryl phosphine oxide,alkyl phosphine sulfide, aryl phosphine sulfide, alkyl aryl phosphinesulfide, alkyl phosphonic acid, aryl phosphonic acid, alkyl phosphinicacid, aryl phosphinic acid, alkyl phosphinous acid, aryl phosphinousacid, phosphate, thiophosphate, phosphite, pyrophosphite, triphosphate,hydrogen phosphate, dihydrogen phosphate, alkyl guanidino, arylguanidino, alkyl aryl guanidino, alkyl carbamate, aryl carbamate, alkylaryl carbamate, alkyl thiocarbamate, aryl thiocarbamate, alkylarylthiocarbamate, alkyl dithiocarbamate, aryl dithiocarbamate, alkylaryldithiocarbamate, bicarbonate, carbonate, perchlorate, chlorate,chlorite, hypochlorite, perbromate, bromate, bromite, hypobromite,tetrahalomanganate, tetrafluoroborate, hexafluoroantimonate,hypophosphite, iodate, periodate, metaborate, tetraaryl borate, tetraalkyl borate, tartrate, salicylate, succinate, citrate, ascorbate,saccharinate, amino acid, hydroxamic acid, thiotosylate, and anions ofion exchange resins, or the corresponding anions thereof. n ispreferably an integer from 0 to 3. W can be a substituted orunsubstituted pyridino moiety. U and V can be independently saturatedcycloalkyl heterocycles having 3 to 20 carbon atoms, more preferably 4to 10 carbon atoms, still more preferably trans-cyclohexanyl fusedrings. U and V can be trans-cyclohexanyl fused rings while W is asubstituted pyridino moiety.

In certain embodiments, the superoxide dismutase mimetic can be thecompound identified as M40403, which can be represented by the formula:

The present invention can involve administration of a ROS scavenger, inparticular, M40403 or a suitable derivative or analog thereof asdescribed above, to a patient in need thereof. Administration of the ROSscavenger, in particular M40403, can be by numerous routes ofadministration well known to those of skill in the art.

Administration of the ROS scavenger can be by any suitable route ofadministration such as, for example, oral, buccal, sublingual,intranasal, inhalation, rectal, intravaginal, transdermal, intradermal,subcutaneous, intramuscular, intraperitoneal, intravenous,intraarterial, intrasternal, intrathecal and the like.

Pharmaceutically acceptable formulations for parenteral or nonparenteraldrug delivery are known in the art such as, for example, are set forthin Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing(1990). For pharmaceutical compositions and methods of treatmentdisclosed herein, dosage forms and administration regimes can bedetermined using standard methods known to skilled artisans, for exampleas set forth in standard references such as Remington: the Science andPractice of Pharmacy (Alfonso R. Gennaro ed. 19th ed. 1995); Hardman, J.G., et al., Goodman & Gilman's The Pharmacological Basis ofTherapeutics, Ninth Edition, McGraw-Hill, 1996; and Rowe, R. C., et al.,Handbook of Pharmaceutical Excipients, Fourth Edition, PharmaceuticalPress, 2003.

Pharmaceutical compositions can be formulated to be compatible with theintended route of administration. Solutions or suspensions used forparenteral, intradermal or subcutaneous application can include: asterile diluent, such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents, such as benzyl alcohol ormethyl parabens; antioxidants, such as ascorbic acid or sodiumbisulfite; chelating agents, such as ethylenediaminetetraacetic acid(EDTA); buffers such as acetates, citrates or phosphates, and agents forthe adjustment of tonicity, such as sodium chloride or dextrose.Suitable carriers include physiological saline, bacteriostatic water,Cremophor® EL (BASF, Parsippany, N.J.) or phosphate buffered saline(PBS). The compositions can be stable during manufacture and storage andpreserved against contamination from microorganisms, such as bacteriaand fungi. Proper fluidity can be maintained, for example, by using acoating such as lecithin; by maintaining the required particle size inthe case of dispersion, and by using surfactants. Various antibacterialand antifungal agents, such as parabens, chlorobutanol, phenol, ascorbicacid, and thimerosal, can control microorganism contamination. Isotonicagents, such as sugars, polyalcohols such as manitol, sorbitol, andsodium chloride can be included in the composition. Compositions thatdelay absorption can be prepared by including such agents as aluminummonostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound (e.g., an SCMP) in an appropriate solvent with one or moreingredient, followed by sterilization. Generally, dispersions areprepared by incorporating the active compound into a sterile vehiclethat contains a basic dispersion medium and any other requiredingredients. Sterile powders for the preparation of sterile injectablesolutions include vacuum- and freeze-drying that yield a powdercontaining the active ingredient and any desired ingredient from asterile solution. The concentration of active drug, i.e. the ROSscavenger, can be from about 0.1% to about 90% by weight, from about 5%to about 20% by weight, from about 5% to about 17% by weight, from about8% to about 14% by weight or, in certain embodiments, about 10% byweight.

Oral compositions generally include an inert diluent or an ediblecarrier. They can be enclosed in gelatin capsules or compressed intotablets. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients and used in the form oftablets, troches, or capsules. Oral compositions can also be preparedusing a fluid carrier for use as a mouthwash, wherein the compound inthe fluid carrier is applied orally. Pharmaceutically compatible bindingagents, and/or adjuvant materials can be included. Tablets, pills,capsules, troches and the like can contain any of the followingingredients, or compounds of a similar nature: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose, a disintegrating agent such as alginic acid,primogel, or corn starch; a lubricant such as magnesium stearate orsterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring. The concentration ofactive drug, i.e. the ROS scavenger, can be from about 0.1% to about 99%by weight, from about 5% to about 95% by weight, from about 10% to about90% by weight, from about 15% to about 85% by weight, from about 20% toabout 80% by weight, from about 25% to about 75% by weight, from about30% to about 70% by weight, from about 35% to about 64% by weight orfrom about 40% to about 60% by weight.

Administration by inhalation, can be by aerosol spray from a nebulizeror a pressurized container that contains a suitable propellant, e.g., agas such as carbon dioxide.

Systemic administration can also be transmucosal or transdermal. Fortransmucosal or transdermal administration, penetrants that can permeatethe target barrier(s) are selected. Transmucosal penetrants includedetergents, bile salts and fusidic acid derivatives. Nasal sprays orsuppositories can be used for transmucosal administration. Fortransdermal administration, the active compounds are formulated intoointments, salves, gels or creams.

The compounds can also be prepared as suppositories (with bases such ascocoa butter and other glycerides) or retention enemas for rectaldelivery.

In various embodiments, the active compounds can be prepared withcarriers that protect the compound against rapid elimination from thebody, such as a controlled release formulation, including implants andmicroencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid (AlzaCorporation; Mountain View, Calif. and Nova Pharmaceuticals, Inc.; LakeElsinore, Calif.). Liposomal suspensions can also be used aspharmaceutically acceptable carriers (Eppstein, 1985).

Oral formulations or parenteral compositions in unit dosage form can becreated to facilitate administration and dosage uniformity. Unit dosageform refers to physically discrete units suited as single doses for asubject to be treated, containing a therapeutically effective quantityof active compound in association with the required pharmaceuticalcarrier. The specification for unit dosage forms are dictated by, anddirectly dependent on, the unique characteristics of the active compoundand the particular desired therapeutic effect, and the inherentlimitations of compounding the active compound.

A typical dose of the ROS scavenger can be from about 0.1 mg up to about1000 mg or from about 0.001 up to about 10 mg/kg body weight. Doses of 5mg/kg and 10 mg/kg administered intraperitoneally have shown to producebeneficial effects in rats treated with type II collagen to inducedarthritis (Salvemini et al., Arthritis & Rheumatism, 44:2909-2921,2001). A dose of 2 mg/kg produced less of an effect that wasnevertheless significantly different from that in placebo animals. Lowdoses of a ROS scavenger can be doses of less than about 5 mg/kg ordoses equal to or less than about 2 mg/kg body weight, in particular, adose of about 0.1 mg, about 0.2 mg, about 0.5 mg, about 0.8 mg, about 1mg, about 2 mg, about 5 mg, about 8 mg, about 10 mg, about 20 mg, about50 mg, about 80 mg, about 100 mg or about 200 mg or about 0.001 mg/kg,about 0.002 mg/kg, about 0.005 mg/kg, about 0.01 mg/kg, about 0.02mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.5mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg or about 4 mg/kg bodyweight.

Total daily doses of the ROS scavenger can be administered in single ordivided doses and in amounts such as, for example, from about 1 to about2 mg/kg body weight daily and more usually about 0.05 to 1 mg/kg. Dosageunit compositions may contain such amounts of submultiples thereof tomake up the total dose. However, one skilled in the art will recognizethat the total dosage will vary on the particular composition theparticular ROS scavenger administered.

Individuals receiving treatment are, typically, human patients, however,patients receiving treatment can also be animal including companionanimal such as dogs and cats, farm animal such as cows, horses, swine aswell as birds and exotic animal such as zoo animals.

The amount of active ingredients that may be combined with the carriermaterials to produce a single dosage form can vary depending upon thehost treated and the particular mode of administration. It will beappreciated that the unit content of active ingredients contained in anindividual dose of each dosage form need not in itself constitute aneffective amount, as the necessary effective amount could be reached byadministration of a number of individual doses. The selection of dosagedepends upon the dosage form utilized, the condition being treated, andthe particular purpose to be achieved according to the determination ofthose skilled in the art.

The dosage regimen for treating a disease condition with the compoundsand/or compositions of this invention can be selected in accordance witha variety of factors, including the type, age, weight, sex, diet andmedical condition of the patient, the route of administration,pharmacological considerations such as the activity, efficacy,pharmacokinetic and toxicology profiles of the particular compoundemployed, whether a drug delivery system is utilized and whether thecompound is administered as part of a drug combination. Thus, the dosageregimen actually employed can, therefore, can deviate from the preferreddosage regimen set forth above.

In various embodiments, the present invention can also involve kits.Such kits can include pharmaceutical compositions and, in addition incertain embodiments, instructions for administration. When supplied as akit, the different components of the composition can be packaged inseparate containers and admixed immediately before use. Such packagingof the components separately can, in certain instances, permit long-termstorage without losing activity of the components. In addition, if morethan one route of administration is intended or more than one schedulefor administration is intended, the different components can be packagedseparately and not mixed prior to use. In various embodiments, thedifferent components can be packaged in one composition foradministration together.

Kits may also include reagents in separate containers such as, forexample sterile water or saline to be added to a lyophilized activecomponent packaged separately. For example, sealed glass ampules maycontain lyophilized ROS scavenger, sterile water, sterile saline orsterile each of which has been packaged under a neutral non-reactinggas, such as nitrogen. Ampules may consist of any suitable material,such as glass, organic polymers, such as polycarbonate, polystyrene,etc., ceramic, metal or any other material typically employed to holdreagents. Other examples of suitable containers include bottles that maybe fabricated from similar substances as ampules, and envelopes that mayconsist of foil-lined interiors, such as aluminum or an alloy. Othercontainers include test tubes, vials, flasks, bottles, syringes, etc.Containers may have a sterile access port, such as a bottle having astopper that can be pierced by a hypodermic injection needle. Othercontainers may have two compartments that are separated by a readilyremovable membrane that upon removal permits the components to mix.Removable membranes may be glass, plastic, rubber, etc.

In certain embodiments, kits can be supplied with instructionalmaterials. Instructions may be printed on paper or other substrate,and/or may be supplied as an electronic-readable medium, such as afloppy disc, mini-CD-ROM, CD-ROM, DVD-ROM, Zip disc, videotape, audiotape, etc. Detailed instructions may not be physically associated withthe kit; instead, a user may be directed to an internet web sitespecified by the manufacturer or distributor of the kit, or supplied aselectronic mail.

EXAMPLES

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following specific examples are offered by wayof illustration and not by way of limiting the remaining disclosure.

Example 1

Objective

The objective of this study is to evaluate the effect of M40403,administered by either ip or topical routes, with 2 different schedules,on the frequency, severity and duration of oral mucositis induced inhamsters by acute radiation.

Summary

M40403 was given as an intraperitoneal (ip) injection at a 30 mg/kg/dosetwice daily (a) from day −1 to day 15, or (b) day −1 to day 3. M40403was also given by ip injection at a dose of 3 mg/kg twice daily from day−1 to day 15. In addition, M40403 was given as a topical dose directedto the buccal mucosa in 0.2 ml doses of either 3 mg/ml or 30 mg/ml twicedaily from day −1 to day 15. The greatest reduction in oral mucositiswas seen in the group treated with M40403 at 30 mg/kg/dose ip twicedaily from day −1 to day 3. This group had a statistically significantreduction in the number of animal days with a mucositis score of 3 orhigher (P<0.001) and significantly lower mean mucositis scores than thecontrol group on days 18 (P=0.041), 20 (P<0.001), 22 (P<0.001), 24(P<0.001) and 26 (P=0.002). No other treatment groups in this studyshowed a reduction in mucositis either by long term (day-1 to day 15) ipdosing or by topical dosing. This study establishes a schedule-dependantdosing method for the treatment of oral mucositis with M40403.

Acute Radiation Model

The acute radiation model in hamsters, developed by the PrincipalInvestigator, has proven to be an accurate, efficient and cost-effectivetechnique to provide a preliminary evaluation of anti-mucositiscompounds (9). The course of mucositis in this model is well defined andresults in peak scores approximately 14-16 Days following radiation. Theacute model has little systemic toxicity, resulting in few hamsterdeaths, thus permitting the use of smaller groups (N=7-8) for initialefficacy studies. It has also been used to study specific mechanisticelements in the pathogenesis of mucositis. Molecules that show efficacyin the acute radiation model may be further evaluated in the morecomplex models of fractionated radiation, chemotherapy, or concomitanttherapy.

In this study, an acute radiation dose of 40 Gy on day 0 wasadministered locally to the cheek pouch. Clinically significantmucositis was observed on days 12 through 28.

Protocol Summary

Forty-eight male Syrian Golden Hamsters were divided randomly into 6groups of 8 animals and given an acute radiation dose of 40 Gy directedto their left buccal cheek pouch. This was accomplished by anesthetizingthe animals and everting the left buccal pouch, while protecting therest of the animal with a lead shield. Test materials were giventopically or by ip injection twice daily as detailed in Table 1.Mucositis was evaluated clinically starting on Day 6, and continued onalternate days until day 28.

Evaluation

Mucositis Evaluation

The grade of mucositis was scored, beginning on day 6, and for everysecond day thereafter, through and including day 28 (for scoring scheme,see Table 2 and FIG. 2 ). The effect on mucositis of each drug treatmentcompared to ip vehicle-treated controls was assessed according to thefollowing parameters:

The difference in the number of days hamsters in each group haveulcerative (score ≥3) mucositis.

On each evaluation day, the number of animals with a blinded mucositisscore of ≥3 in each drug treatment group was compared to thevehicle-treated control group. Differences were compared on a cumulativebasis and statistical significance was determined by chi-squareanalysis. Efficacy, in this analysis, is defined as a significantreduction in the number of days that a group of animals had ulcerations(scores ≥3) when compared to the control group.

TABLE 2 Table 2 ACT-02: Mucositis Scoring. Score: Description: 0 Pouchcompletely healthy. No erythema or vasodilation. 1 Light to severeerythema and vasodilation. No erosion of mucosa. 2 Severe erythema andvasodilation. Erosion of superficial aspects of mucosa leaving denudedareas. Decreased stippling of mucosa. 3 Formation of off-white ulcers inone or more places. Ulcers may have a yellow/gray due to pseudomembrane.Cumulative size of ulcers should equal about ¼ of the pouch. Severeerythema and vasodilation. 4 Cumulative seize of ulcers should equalabout ½ of the pouch. Loss of pliability. Severe erythema andvasodilation. 5 Virtually all of pouch is ulcerated. Loss of pliability(pouch can only partially be extracted from mouth).

Rank Sum Differences in Daily Mucositis Scores.

For each evaluation day the scores of the control group were compared tothose of the treated groups using non-parametric rank sum analysis.Treatment success was considered as a statistically significant loweringof scores in the treated group on 2 or more days from day 6 to day 28.

Weights and Survival

All animals were weighed daily and their survival recorded, in order toassess possible differences in animal weight among treatment groups asan indication for mucositis severity and/or possible toxicity resultingfrom the treatments.

Study Design

All forty-eight (48) male Syrian Golden Hamsters were given an acuteradiation dose of 40 Gy directed to their left buccal cheek pouch. Thiswas accomplished by anesthetizing the animals and everting the leftbuccal pouch, while protecting the rest of the animal with a leadshield. Test materials were given either topically or by ip injectiontwice daily as detailed in Table 1. Mucositis was evaluated clinicallystarting on day 6, and continuing on alternate days until day 28. Thestudy timeline is depicted in FIG. 1 . Dose levels were determined basedon the results of a previous acute toxicity study (data not shown), andthe levels shown in Table 1.

TABLE 1 Table 1. ACT-02. Study Design Group Number of Treatment VolumeNumber Animals Treatment Schedule* (mL) 1 8 males Vehicle, ip, bid Day−1 to 15 Adjust per body weight 2 8 males M40403, ip, bid Day −1 to 15Adjust per 3 mg/kg body weight 3 8 males M40403, ip, bid Day −1 to 15Adjust per 30 mg/kg body weight 4 8 males M40403, topical, bid Day −1 to15 0.2 ml per 3 mg/ml dose 5 8 males M40403, topical, bid Day −1 to 150.2 ml per 30 mg/ml dose 6 8 males M40403, ip, bid Day −1 to 3 Adjustper 30 mg/kg body weight *The first dose on day 0 was performed 30minutes prior to radiation. The second dose was given at least 4 hoursafter radiation.

At the end of the study on day 28, the animals in group 1 were used in amodified pK study as follows: Two animals were injected with vehicle andblood was drawn 30 minutes after the injection. Six animals wereinjected with 30 mg/kg of M40403. At 15, 30 and 90 minutes postinjection, 2 animals from this group were sacrificed and blood wasobtained by cardiac puncture. Blood was collected in lithium heparin,kept on ice for 30 minutes and the plasma was obtained aftercentrifugation. Plasma was transferred to labeled tubes, snap frozen inliquid nitrogen and shipped to ActivBiotics.

Material and Methods

Location of Study Performance

The study was performed at Biomodels AAALAC accredited facility inCambridge Mass. The IACUC approval number 04-0624-2 for this study wasobtained from Biomodels IACUC.

Animals

Male LVG Syrian Golden Hamsters (Charles River Laboratories), aged 5 to6 weeks, with average body weight of 84.1 g at study commencement, wereused. Animals were individually numbered using an ear punch and housedin small groups of approximately 8 animals per cage. Animals wereacclimatized prior to study commencement. During this period of 2 days,the animals were observed daily in order to reject animals thatpresented in poor condition.

Housing

The study was performed in animal rooms provided with filtered air at atemperature of 70° F.+/−5° F. and 50%+/−20% relative humidity. Animalrooms were set to maintain a minimum of 12 to 15 air changes per hour.The room was on an automatic timer for a light/dark cycle of 12 hours onand 12 hours off with no twilight. Bed-O-Cobs® bedding was used. Beddingwas changed a minimum of once per week. Cages, tops, bottles, etc. werewashed with a commercial detergent and allowed to air dry. A commercialdisinfectant was used to disinfect surfaces and materials introducedinto the hood. Floors were swept daily and mopped a minimum of twiceweekly with a commercial detergent. Walls and cage racks were sponged aminimum of once per month with a dilute bleach solution. A cage card orlabel with the appropriate information necessary to identify the study,dose, animal number and treatment group marked all cages. Thetemperature and relative humidity was recorded during the study, and therecords were retained.

Diet

Animals were fed with a Purina Labdiet® 5061 rodent diet and water wasprovided ad libitum. Animal randomization and allocations.

Animals were randomly and prospectively divided into eight (8) treatmentgroups prior to irradiation. Each animal was identified by an ear punchcorresponding to an individual number. For more consistentidentification, ear punch numbering was used rather than tagging, sincetags may become dislodged during the course of the study. A cage cardwas used to identify each cage and was marked with the study number,treatment group number and animal numbers.

Dosing and Drug Application

Dosing solutions were made immediately prior to use. Aseptic techniquewas used for all preparation procedures. A 26-mM sodium bicarbonatebuffer solution was prepared as the vehicle. The resultant pH wasapproximately 8.1 to 8.3.

Mucositis Induction

Mucositis was induced using a standardized acute radiation protocol. Asingle dose of radiation (40 Gy/dose) was administered to all animals onday 0. Radiation was generated with a 250 kilovolt potential (15-ma)source at a focal distance of 50 cm, hardened with a 0.35 mm Cufiltration system. Irradiation targeted the left buccal pouch mucosa ata rate of 3.2 Gy/minute. Prior to irradiation, animals were anesthetizedwith an intra-peritoneal injection of Ketamine (160 mg/kg) and Xylazine(8 mg/kg). The left buccal pouch was everted, fixed and isolated using alead shield.

Mucositis Scoring

The mucositis score, weight change and survival were measured throughoutthe study as described above. For the evaluation of mucositis, theanimals were anesthetized with isoflurane and the left pouch everted.Mucositis was scored visually by comparison to a validated photographicscale (FIG. 2 ), ranging from 0 for normal, to 5 for severe ulceration(clinical scoring). In descriptive terms, this scale is defined asfollows:

A score of 1-2 is considered to represent a mild stage of the disease,whereas a score of 3-5 is considered to indicate moderate to severemucositis. Following visual scoring, a photograph was taken of eachanimal's mucosa using a standardized technique. At the conclusion of theexperiment, all films were developed and the photographs randomlynumbered. At least two independent trained observers graded thephotographs in blinded fashion using the above described scale (blindedscoring).

Results and Discussion

Survival

Five deaths occurred during this study. Two animals, hamsters 8 and 23,in the vehicle control group and the group treated with M40403 at 30mg/kg twice a day from day −1 to day 15 died on day 0 from apparentanesthesia overdoses. In addition, two animals (hamsters 45 and 46) diedin the group treated with M40403 at 30 mg/kg twice daily from day −1 today 3. Hamster 45 died during radiation and hamster 46 was found deadthe following morning. Both deaths appeared to be the result ofanesthesia overdose, in the case of hamster 46 the response was delayed.The occurrence of anesthesia deaths in this model is anticipated in theexperimental design. Hamster 19, in the group treated ip with M40403 at30 mg/kg twice a day from day −1 to day 15 died on day 12. This deathresulted after an extended period of failure to gain weight and mayreflect toxicity of this dosing regimen as all animals in this groupshowed lack of weight gain (see FIGS. 3 and 4 below).

Weight Change (FIGS. 3 and 4 ).

The percent daily weight change for each group is shown in FIG. 3 . Thegroups treated by ip injection were groups 1, 2, 3 and 6. The controlanimals (group 1) gained an average of 64.0% of their starting weightsby the end of the study. The animals treated ip with M40403 at 3mg/kg/dose twice daily from day −1 to day 15 (group 2) gained an averageof 66.0% of their starting weight during the study. The group treated ipwith M40403 at 30 mg/kg/dose twice daily from day −1 to day 15 (group 3)gained an average of 33.9% of their starting weight by day 28. The grouptreated ip with M40403 at 30 mg/kg/dose twice daily from day 1 to day 3gained an average of 54.7% of their starting weight during the study. Inboth groups treated by ip injection with 30 mg/kg M40403, there was ageneral lack of weight gain during dosing.

In the 2 groups treated topically with M40403 (groups 4 and 5) there wasno apparent change in weight gain when compared to the control group.The animals treated topically with M40403 at 3 mg/ml twice daily fromday −1 to day 15 gained an average of 65.8% of their starting weight byday 28. The group treated topically with M40403 at 30 mg/ml twice dailyfrom day −1 to day 15 gained an average of 71.9% of their startingweight during the study.

The significance of these differences was evaluated by calculating themean area under the curve for the percentage weight gain for each animaland comparing the groups using a OneWay ANOVA test. There was asignificant difference between the control group and group 3 treated byip injection with M40403 twice daily (30 mg/kg) on days −1 to 15(P<0.001). There was also a significant difference between the controlgroup and the group treated by ip injection with M40403 twice daily at30 mg/kg/dose from day −1 to day 3 (P=0.018). No other significantdifferences were seen. The topical treatment groups (groups 4 and 5)showed no significant weight differences when compared with the controlgroup. The AUC data is shown in FIG. 4 . Many of the groups with asignificant reduction in weight gain are the same groups in which animaldeaths were observed.

TABLE 4 Table 4. ACT-02. The significance of group differences observedin daily mucositis scores was determined using the Mann-Whimey rank sumtest. This nonparametric statistic is appropriate for the visualmucositis scoring scale. The p values for each calculation are shown.Day Group Comparison 6 8 10 12 14 16 18 20 22 24 26 28 Control v 0.0990.630 0.950 0.286 0.983 0.630 0.436 0.571 0.754 0.325 0.516 0.070 M40403ip 3 mg/kg day −1 to 15 Control v 0.055 0.981 0.981 0.055 0.856 0.9380.221 0.622 0.698 0.067 0.979 0.225 M40403 ip 30 mg/kg day −1 to 15Control v 0.099 0.099 0.630 0.463 0.463 0.438 0.983 0.983 0.163 0.6320.517 0.139 M40403 top 3 mg/ml day −1 to 15 Control v 0.630 0.099 0.0020.573 0.465 0.571 0.884 0.884 0.573 0.632 0.754 0.884 M40403 top 30mg/ml day −1 to 15 Control v 0.127 0.059 0.548 0.936 0.221 0.312 0.041<0.001 <0.001 <0.001 0.002 0.551 M40403 ip 30 mg/kg day −1 to 3

Mucositis (FIGS. 5 & 6 , Tables 3 & 4)

Mean daily mucositis scores for each group are shown in FIG. 5 . Thegroups treated by ip injection were groups 1, 2, 3 and 6. The controlanimals (group 1) had a peak mean mucositis score of 2.8 which occurredon day 16. The animals treated with M40403 at 3 mg/kg/dose ip twicedaily from day −1 to day 15 (group 2) had a peak mucositis score of 2.8on day 18, and the overall progression of mucositis severity in thisgroup was very similar to that observed in the control group. The grouptreated with M40403 at 30 mg/kg/dose twice daily from day −1 to day 15(group 3) had a peak mucositis score of 3.0 on day 18 and had amucositis progression that was indistinguishable from that observed ingroups 1 and 2. The group treated with M40403 at 30 mg/kg/dose ip twicedaily from day −1 to day 3 had a peak mucositis score of 3.0 on day 14,but from day 16 to day 28, the mucositis severity in this groupdecreased much more rapidly than the control group suggesting that thisschedule of treatment was efficacious.

In the 2 groups treated topically with M40403 (groups 4 and 5) there wasno apparent effect of treatment on the course of mucositis. The animalstreated topically with M40403 at 3 mg/ml twice daily from day −1 to day15 had mucositis scores that closely paralleled those in the controlgroup. The group treated topically with M40403 at 30 mg/ml twice dailyfrom day −1 to day 15 showed a reduction of mucositis severity on day10. However, from day 12 to the end of the study, the scores in thisgroup were only slightly less than those in the control group.

The significance of the reductions in the mucositis scores seen in thegroups treated with M40403 were evaluated by calculating the percentageof animal days with a score of 3 or higher. The results of this analysisare shown in FIG. 6 and Table 3. In the control group, the percentage ofanimal days with a mucositis score of 3 or higher was 31%. Treatment byip injection with M40403 at 3 mg/kg/dose twice daily from day −1 to day15 resulted in a percentage of animal days with a score of 3 or higherof 34%. Treatment by ip injection with M40403 at 30 mg/kg/dose twicedaily from day to −1 to day 15 resulted in 37% percent of animal dayswith a score of 3 or higher. Treatment by ip injection with M40403 at 30mg/kg twice daily from day −1 to day 3 (group 6) resulted in a decreasein the number of animal days with a score of 3 or higher to 17%.

TABLE 3 Table 3. ACT-02. Chi-square analysis of the total number of daysthe animals in each group spent with a mucositis score of 3 or more.This statistic is a measure of severity of ulceration, a clinicallyimportant outcome. Chi Sq Group Days >=3 Days <3 Total Days % Days >=3 vcontrol P Value Vehicle ip control 52 116 168 0.31 — — day −1 to 15M40403 ip 3 mg/kg 66 126 192 0.34 0.3440 0.563 day −1 to 15 M40403 ip 30mg/kg 56 96 152 0.37 0.9890 0.320 day −1 to 15 M40403 top 3 mg/ml 73 119192 0.38 1.6760 0.196 day −1 to 15 M40403 top 30 mg/ml 64 128 192 0.330.136 0.712 day −1 to 15 M40403 ip 30 mg/kg 24 120 144 0.17 7.83 0.005day −1 to 3

In the animals receiving M40403 topically, there were no apparentreductions of mucositis severity at either dosing level. Topicaltreatment with M40403 at 3 mg/ml twice daily from day −1 to day 15resulted in an increase in the number of animal days with a score of 3or higher to 38%. Topical treatment with M40403 at 30 mg/ml twice dailyfrom days −1 to 15 resulted in 33% of animal days with a score of 3 orhigher.

When compared using a chi-squared test, the group treated by ipinjection with M40403 at 30 mg/kg/dose twice daily on days −1 to day 3had the greatest reduction in mucositis and significantly fewer dayswith a score of 3 or higher (P=0.005). No other study group exhibited areduction in mucositis severity and no group demonstrated a significantdifference in mucositis severity by this analysis.

Further analysis of the mucositis scores was performed by comparing thescores for the M40403 treated groups with the control on each day ofscoring using the Mann-Whitney Rank Sum test. The results of thisanalysis are shown in Table 4. The group treated by ip injection withM40403 at 30 mg/kg/dose twice daily on days −1 to day 3 (group 6) hadthe greatest reduction in mucositis and significantly lower scores thanthe control group on days 18 (P=0.041), 20 (P<0.001), 22 (P<0.001), 24(P<0.001) and 26 (P=0.002). No other study group had more than a singleday showing a significant lowering of mucositis severity. Given thatgroup 2 received the same dose of drug for a longer duration, theseresults suggest that the schedule of dosing M40403 is crucial inestablishing an effective treatment for mucositis.

Conclusions

1. Based on observations of mortality and body weight, ip injections ofM40403, twice daily, at 30 mg/kg appear to show some toxicity. Thelonger dosing in group 3 resulted in mortality and significant weightloss. When dosed for the shorter period of day −1 to day 3 (group 6),the weight loss was reversed after the cessation of dosing.

2. Topical dosing of M40403 did not appear to have any effect on eitherweight or mucositis severity. It appears the topical dosing, in theformulation used here, is an ineffective method of delivery of M40403 inthis model.

3. The group treated by ip injection with M40403 at 30 mg/kg/dose twicedaily on days 1 to 3 had a statistically significant reduction in thenumber of animal days with a mucositis score of 3 or higher (P=0.005)and significantly lower mucositis scores than the control group on days18 (P=0.041), 20 (P<0.001), 22 (P<0.001), 24 (P<0.001) and 26 (P=0.002).This result suggests that M40403 may be an effective agent in thetreatment of oral mucositis. Further studies of dose and schedule may berequired to optimize the efficacy of M40403.

Example 2—Repeat of day −1 to 3 of 30 mg/kg IV of Example 1 study

Acute Radiation Model

The acute radiation model in hamsters, developed by the PrincipalInvestigator, has proven to be an accurate, efficient and cost-effectivetechnique to provide a preliminary evaluation of anti-mucositiscompounds (9). The course of mucositis in this model is well defined andresults in peak scores approximately 14-16 Days following radiation. Theacute model has little systemic toxicity, resulting in few hamsterdeaths, thus permitting the use of smaller groups (N=7-8) for initialefficacy studies. It has also been used to study specific mechanisticelements in the pathogenesis of mucositis. Molecules that show efficacyin the acute radiation model may be further evaluated in the morecomplex models of fractionated radiation, chemotherapy, or concomitanttherapy.

In this study, an acute radiation dose of 40 Gy on day 0 wasadministered locally to the cheek pouch. Clinically significantmucositis was observed on days 12 through 28.

Protocol Summary

Seventy-two male Syrian Golden Hamsters were divided randomly into 9groups of 8 animals and given an acute radiation dose of 40 Gy directedto their left buccal cheek pouch. This was accomplished by anesthetizingthe animals and everting the left buccal pouch, while protecting therest of the animal with a lead shield. Test materials were giventopically or by ip injection twice daily as detailed in Table 5.Mucositis was evaluated clinically starting on Day 6, and continued onalternate days until day 28.

TABLE 5 Table 1. ACT-03. Study Design Group Number of Treatment VolumeNumber Animals Treatment Schedule* (mL) 1 8 males Vehicle, ip, bid Day−1 to 3 Adjust per body weight 2 8 males M40403, ip, QD Day −1 to 3Adjust per 30 mg/kg body weight 3 8 males M40403, ip, bid Day −1 to 3Adjust per 3 mg/kg body weight 4 8 males M40403, ip, bid Day −1 to 3Adjust per 10 mg/kg body weight 5 8 males M40403, ip, bid Day −1 to 3Adjust per 30 mg/kg body weight 6 8 males M40403, ip, QD Day 0 to 3Adjust per 30 mg/kg body weight 7 8 males M40403, ip, bid Day 0 to 3Adjust per 30 mg/kg body weight 8 8 males M40403, ip, bid Day 0 Adjustper 30 mg/kg body weight 9 8 males M40403, ip, bid Day 0 and Day 7Adjust per 30 mg/kg body weight *For BID dosing the first dose on day 0will be performed 30 minutes prior to radiation. The second dose will begiven at least 4 hours after radiation. For QD dosing, the dose will beadministered on day 0 at 30 minutes prior to irradiation.

Evaluation

Mucositis Evaluation

The grade of mucositis was scored, beginning on day 6, and for everysecond day thereafter, through and including day 28 (for scoring scheme,see Table 6 and FIG. 8 ). The effect on mucositis of each drug treatmentcompared to ip vehicle-treated controls was assessed according to thefollowing parameters:

The difference in the number of days hamsters in each group haveulcerative (score ≥3) mucositis.

On each evaluation day, the number of animals with a blinded mucositisscore of ≥3 in each drug treatment group was compared to thevehicle-treated control group. Differences were compared on a cumulativebasis and statistical significance was determined by chi-squareanalysis. Efficacy, in this analysis, is defined as a significantreduction in the number of days that a group of animals had ulcerations(scores ≥3) when compared to the control group.

TABLE 6 Table 2 ACT-03: Mucositis Scoring. Score: Description: 0 Pouchcompletely healthy. No erythema or vasodilation. 1 Light to severeerythema and vasodilation. No erosion of mucosa. 2 Severe erythema andvasodilation. Erosion of superficial aspects of mucosa leaving denudedareas. Decreased stippling of mucosa. 3 Formation of off-white ulcers inone or more places. Ulcers may have a yellow/gray due to pseudomembrane.Cumulative size of ulcers should equal about ¼ of the pouch. Severeerythema and vasodilation. 4 Cumulative seize of ulcers should equalabout ½ of the pouch. Loss of pliability. Severe erythema andvasodilation. 5 Virtually all of pouch is ulcerated. Loss of pliability(pouch can only partially be extracted from mouth).

Rank Sum Differences in Daily Mucositis Scores.

For each evaluation day the scores of the control group were compared tothose of the treated groups using non-parametric rank sum analysis.Treatment success was considered as a statistically significant loweringof scores in the treated group on 2 or more days from day 6 to day 28.

Weights and Survival

All animals were weighed daily and their survival recorded, in order toassess possible differences in animal weight among treatment groups asan indication for mucositis severity and/or possible toxicity resultingfrom the treatments.

Study Design

All seventy-two (72) male Syrian Golden Hamsters were given an acuteradiation dose of 40 Gy directed to their left buccal cheek pouch. Thiswas accomplished by anesthetizing the animals and everting the leftbuccal pouch, while protecting the rest of the animal with a leadshield. Test materials were given either topically or by ip injectiontwice daily as detailed in Table 5. Mucositis was evaluated clinicallystarting on day 6, and continuing on alternate days until day 28. Thestudy timeline is depicted in FIG. 7 . Dose levels were determined basedon the results of a previous acute toxicity study (data not published),and in the prior mucositis study of Example 1, shown in Table 5.

Material and Methods

Location of Study Performance

The study was performed at Biomodels AAALAC accredited facility inCambridge Mass. The IACUC approval number 04-0624-2 for this study wasobtained from Biomodels IACUC.

Animals

Male LVG Syrian Golden Hamsters (Charles River Laboratories), aged 5 to6 weeks, with average body weight of 92.7 at study commencement, wereused. Animals were individually numbered using an ear punch and housedin small groups of approximately 8 animals per cage. Animals wereacclimatized prior to study commencement. During this period of 3 days,the animals were observed daily in order to reject animals thatpresented in poor condition.

Housing

The study was performed in animal rooms provided with filtered air at atemperature of 70° F.+/−5° F. and 50%+/−20% relative humidity. Animalrooms were set to maintain a minimum of 12 to 15 air changes per hour.The room was on an automatic timer for a light/dark cycle of 12 hours onand 12 hours off with no twilight. Bed-O-Cobs® bedding was used. Beddingwas changed a minimum of once per week. Cages, tops, bottles, etc. werewashed with a commercial detergent and allowed to air dry. A commercialdisinfectant was used to disinfect surfaces and materials introducedinto the hood. Floors were swept daily and mopped a minimum of twiceweekly with a commercial detergent. Walls and cage racks were sponged aminimum of once per month with a dilute bleach solution. A cage card orlabel with the appropriate information necessary to identify the study,dose, animal number and treatment group marked all cages. Thetemperature and relative humidity was recorded during the study, and therecords were retained.

Diet

Animals were fed with a Purina Labdiet® 5061 rodent diet and water wasprovided ad libitum. Animal randomization and allocations.

Animals were randomly and prospectively divided into eight (8) treatmentgroups prior to irradiation. Each animal was identified by an ear punchcorresponding to an individual number. For more consistentidentification, ear punch numbering was used rather than tagging, sincetags may become dislodged during the course of the study. A cage cardwas used to identify each cage and was marked with the study number(ACT-03), treatment group number and animal numbers.

Dosing and Drug Application

Dosing solutions were made immediately prior to use. Aseptic techniquewas used for all preparation procedures. A 26-mM sodium bicarbonatebuffer solution was prepared as the vehicle. The resultant pH wasapproximately 8.1 to 8.3.

Mucositis Induction

Mucositis was induced using a standardized acute radiation protocol. Asingle dose of radiation (40 Gy/dose) was administered to all animals onday 0. Radiation was generated with a 250 kilovolt potential (15-ma)source at a focal distance of 50 cm, hardened with a 0.35 mm Cufiltration system. Irradiation targeted the left buccal pouch mucosa ata rate of 3.2 Gy/minute. Prior to irradiation, animals were anesthetizedwith an intra-peritoneal injection of Ketamine (160 mg/kg) and Xylazine(8 mg/kg). The left buccal pouch was everted, fixed and isolated using alead shield.

Mucositis Scoring

The mucositis score, weight change and survival were measured throughoutthe study as described above. For the evaluation of mucositis, theanimals were anesthetized with isoflurane and the left pouch everted.Mucositis was scored visually by comparison to a validated photographicscale (FIG. 8 ), ranging from 0 for normal, to 5 for severe ulceration(clinical scoring). In descriptive terms, this scale is defined asfollows:

A score of 1-2 is considered to represent a mild stage of the disease,whereas a score of 3-5 is considered to indicate moderate to severemucositis. Following visual scoring, a photograph was taken of eachanimal's mucosa using a standardized technique. At the conclusion of theexperiment, all films were developed and the photographs randomlynumbered. At least two independent trained observers graded thephotographs in blinded fashion using the above-described scale (blindedscoring).

Results and Discussion

Survival

Seven deaths occurred during this study, all on the day of radiation(Day 0). Two animals each died in the group treated with M40403 at 30mg/kg once daily from day −1 to day 3, the group treated with M40403 at30 mg/kg twice daily from day −1 to day 3 and the group treated withM40403 at 30 mg/kg once daily from day 0 to day 3. One animal died inthe group treated with M40403 at 30 mg/kg once daily on day 0 and day 7

Weight Change (FIGS. 9 and 10 ).

The percent daily weight change for each group is shown in FIG. 9 . Thecontrol animals (group 1) gained an average of 62.5% of their startingweights by the end of the study. The animals treated ip with M40403 at30 mg/kg/dose once daily from day −1 to day 3 (group 2) gained anaverage of 60.7% of their starting weight during the study. The grouptreated ip with M40403 at 3 mg/kg/dose twice daily from day −1 to day 3(group 3) gained an average of 59.3% of their starting weight by day 28.The group treated ip with M40403 at 10 mg/kg/dose twice daily from day−1 to day 3 (group 4) gained an average of 56.2% of their startingweight during the study. The group treated ip with M40403 at 30mg/kg/dose twice daily from day −1 to day 3 (group 5) gained an averageof 52.9% of their starting weight during the study. The group treated ipwith M40403 at 30 mg/kg/dose once daily from day 0 to day 3 (group 6)gained an average of 54.8% of their starting weight during the study.The group treated ip with M40403 at 30 mg/kg/dose twice daily from day 0to day 3 (group 7) gained an average of 58.1% of their starting weightduring the study. The group treated ip with M40403 at 30 mg/kg/dosetwice daily on day 0 (group 8) gained an average of 59.3% of theirstarting weight during the study. The group treated ip with M40403 at 30mg/kg/dose twice daily on day 0 and on day 7 (group 9) gained an averageof 57.3% of their starting weight during the study.

The significance of these differences was evaluated by calculating themean area under the curve for the percentage weight gain for each animaland comparing the groups using a One-Way ANOVA test. There weresignificant differences between the vehicle control group and the grouptreated with M40403 at 30 mg/kg/dose once daily from day −1 to day 3(P=0.039), he group treated with M40403 at 3 mg/kg/dose twice daily fromday −1 to day 3 (P=0.040), the group treated with M40403 at 10mg/kg/dose twice daily from day −1 to day 3 (0.018), the group treatedwith M40403 at 30 mg/kg/dose twice daily from day −1 to day 3 (P<0.001),the group treated with M40403 at 30 mg/kg/dose once daily from day 0 today 3 (P=0.009) and the group treated with M40403 at 30 mg/kg/dose twicedaily from day 0 to day 3 (P=0.002). The results of this analysis areshown in FIG. 10 .

Mucositis (FIGS. 11 & 12 , Tables 7 & 8)

Mean daily mucositis scores for each group are shown in FIG. 11 . Thecontrol animals (group 1) had a peak mean mucositis score of 3.1 on day16. The animals treated ip with M40403 at 30 mg/kg/dose once daily fromday −1 to day 3 (group 2) had a peak mean mucositis score of 2.8 on day16. The group treated ip with M40403 at 3 mg/kg/dose twice daily fromday −1 to day 3 (group 3) had a peak mean mucositis score of 2.9, whichoccurred on days 16 and 18. The group treated ip with M40403 at 10mg/kg/dose twice daily from day −1 to day 3 (group 4) had a peak meanmucositis score of 3.0 on day 16. The group treated ip with M40403 at 30mg/kg/dose twice daily from day −1 to day 3 (group 5) had a peak meanmucositis score of 2.8 on day 16. The group treated ip with M40403 at 30mg/kg/dose once daily from day 0 to day 3 (group 6) had a peak meanmucositis score of 3.2 on day 16. The group treated ip with M40403 at 30mg/kg/dose twice daily from day 0 to day 3 (group 7) had a peak meanmucositis score of 2.2 on day 16. The group treated ip with M40403 at 30mg/kg/dose twice daily on day 0 (group 8) had a peak mean mucositisscore of 2.4 on day 14. The group treated ip with M40403 at 30mg/kg/dose twice daily on day 0 and on day 7 (group 9) had a peak meanmucositis score of 2.4 which occurred on days 16 and 18.

The significance of the reductions in the mucositis scores seen in thegroups treated with M40403 were evaluated by calculating the percentageof animal days with a score of 3 or higher. The results of this analysisare shown in FIG. 12 and Table 7. In the control group, the percentageof animal days with a mucositis score of 3 or higher was 36.5%.Treatment by ip injection with M40403 at 30 mg/kg/dose once daily fromday −1 to day 3 (group 2) or M40403 at 3 mg/kg/dose twice daily from day−1 to day 3 (group 3) resulted in a percentage of animal days with ascore of 3 or higher of 25%. Treatment with M40403 at 10 mg/kg/dosetwice daily from day −1 to day 3 (group 4) resulted in a percentage ofanimal days with a score of 3 or higher of 29.2%. Treatment with M40403at 30 mg/kg/dose twice daily from day −1 to day 3 (group 5) resulted ina percentage of animal days with a score of 3 or higher of 22.2%.Treatment with M40403 at 30 mg/kg/dose once daily from day 0 to day 3(group 6) resulted in a percentage of animal days with a score of 3 orhigher of 30.6%. Treatment with M40403 at 30 mg/kg/dose twice daily fromday 0 to day 3 (group 7) resulted in a percentage of animal days with ascore of 3 or higher of 9.4%. Treatment with M40403 at 30 mg/kg/dosetwice daily on day 0 (group 8) resulted in a percentage of animal dayswith a score of 3 or higher of 13.5%. Treatment with M40403 at 30mg/kg/dose twice daily on day 0 and on day 7 (group 9) resulted in apercentage of animal days with a score of 3 or higher of 15.5%. Whencompared using a chi-squared test, significant reductions in the numberof animal days with a score of 3 or higher were seen in the groupstreated with M40403 at 30 mg/kg/dose once daily from day −1 to day 3(group 2, P=0.034), M40403 at 3 mg/kg/dose twice daily from day −1 today 3 (group 3, P=0.020), M40403 at 30 mg/kg/dose twice daily from day−1 to day 3 (group 5, P=0.007), M40403 at 30 mg/kg/dose twice daily fromday 0 to day 3 (group 7, P<0.001), M40403 at 30 mg/kg/dose twice dailyon day 0 (group 8, P<0.001) and M40403 at 30 mg/kg/dose twice daily onday 0 and on day 7 (group 9, P<0.001). This data is shown in FIG. 12 andTable 7.

TABLE 7 Table 3. ACT-03. Chi-square analysis of the total number of daysthe animals in each group spent with a mucositis score of three or more.This statistic is a measure of severity of ulceration, a clinicallyimportant outcome. Chi Sq Group Days >=3 Days <3 Total Days % Days >=3 vcontrol P Value Vehicle ip control bid 70 122 192 36.46% — — day −1 to 3M40403 ip 30 mg/kg qd 36 108 144 25.00% 4.4860 0.034 day −1 to 3 M40403ip 3 mg/kg bid 48 144 192 25.00% 5.3950 0.020 day −1 to 3 M40403 ip 10mg/kg bid 56 136 192 29.17% 1.1996 0.158 day −1 to 3 M40403 ip 30 mg/kgbid 32 112 144 22.22% 7.229 0.007 day −1 to 3 M40403 ip 30 mg/kg qd 44100 144 30.56% 1.029 0.310 day 0 to 3 M40403 ip 30 mg/kg bid 18 174 1929.38% 38.3440 <0.001 day 0 to 3 M40403 ip 30 mg/kg bid 26 166 192 13.54%25.681 <0.001 day 0 M40403 ip 30 mg/kg bid 26 142 168 15.48% 19.113<0.001 day 0 & 7

Further analysis of the mucositis scores was performed by comparing thescores for the M40403 treated groups with the control on each day ofscoring using the Mann-Whitney Rank Sum test. The results of thisanalysis are shown in Table 8. The groups treated with M40403 at 30mg/kg/dose once daily from day −1 to day 3 (group 2), M40403 at 10mg/kg/dose twice daily from day −1 to day 3 (group 4) and M40403 at 30mg/kg/dose once daily from day 0 to day 3 (group 6) did not show anydays with significant differences relative to controls. The scores forthe group treated with M40403 at 3 mg/kg/dose twice daily from day −1 today 3 (group 3) were significant different from controls on days 14(P=0.013), 22 (P=0.047) and 28 (P=0.012). The group treated with M40403at 30 mg/kg/dose twice daily from day −1 to day 3 (group 5) wassignificant different from controls on days 24 (P=0.048). The grouptreated with M40403 at 30 mg/kg/dose twice daily from day 0 to day 3(group 7) had significantly lower scores than the control group on days14 (P<0.001), 16 (P=0.001), 18 (P=0.007), 20 (P=0.001), 22 (P<0.001), 24(P=0.006), 26 (P=0.001) and 28 (P=0.012). The group treated with M40403at 30 mg/kg/dose twice daily on day 0 (group 8) had significantly lowerscores than the control group on days 16 (P=0.001), 18 (P=0.033), 20(P=0.002), 22 (P<0.001), 24 (P=0.010), 26 (P<0.001) and 28 (P=0.009).The group treated with M40403 at 30 mg/kg/dose twice daily on day 0 andon day 7 (group 9) had significantly lower scores than the control groupon days 14 (P=0.004), 16 (P=0.047), 20 (P<0.001), 22 (P=0.015) and 26(P=0.047).

TABLE 8 Table 4. ACT-03. The significance of group differences observedin daily mucositis scores was determined using the Mann-Whitney rank sumtest. This nonparametric statistic is appropriate for the visualmucositis scoring scale. The p values for each calculation are shown.Significant improvements are shown underlined. Day Group Comparison 6 810 12 14 16 18 20 22 24 26 28 Control v 0.467 0.655 0.944 0.499 0.0970.231 0.233 0.315 0.235 0.294 0.273 0.253 M40403 ip 30 mg/kg qd day −1to 3 Control v 0.985 0.231 0.985 0.748 0.013 0.297 0.865 0.459 0.0470.610 0.283 0.012 M40403 ip 3 mg/kg bid day −1 to 3 Control v 0.2300.985 0.985 0.865 0.506 0.955 0.437 0.414 0.354 0.595 0.463 0.584 M40403ip 10 mg/kg bid day −1 to 3 Control v 0.725 0.655 0.410 0.428 0.0970.141 0.216 0.097 0.170 0.048 0.053 0.066 M40403 ip 30 mg/kg bid day −1to 3 Control v 0.981 0.944 0.798 0.834 0.361 0.870 0.592 0.981 0.4370.388 0.362 0.798 M40403 ip 30 mg/kg qd day 0 to 3 Control v 0.776 0.5550.472 0.940 <0.001  0.001 0.007 0.001 <0.001  0.006 0.001 0.012 M40403ip 30 mg/kg bid day 0 to 3 Control v 0.776 0.985 0.374 0.519 0.061 0.0010.033 0.002 <0.001  0.010 <0.001  0.009 M40403 ip 30 mg/kg bid day 0Control v 0.415 0.721 0.156 0.851 0.004 0.047 0.091 <0.001  0.015 0.1630.047 0.219 M40403 ip 30 mg/kg bid day 0 & 7 CONCLUSIONS 1. Based onobservations of body weight, ip injections of M40403, appear to showsome toxicity. The only groups that did not exhibit some statisticallysignificant reductions in growth rate were those dosed with M40404 onday 0 only or on day 0 and day 7. Some mortality was noted on the day ofradiation, but it is not clear whether this was related to treatmentwith M40403, or simply accidental death during the anesthesia process 2.The groups treated with M40403 at 30 mg/kg/dose once daily from day −1to day 3, M40403 at 10 mg/kg/dose twice daily from day −1 to day 3 orM40403 at 30 mg/kg/dose once daily from day 0 to day 3 did not generallyshow any significant reduction in the course of mucositis relative tocontrols, although the group treated with M40403 at 30 mg/kg/dose oncedaily from day −1 to day 3 showed a significant reduction in the numberof animals days with a score of 3 or higher (P = 0.034). 3. The grouptreated with M40403 at 3 mg/kg/dose twice daily from day −1 to day 3 hadsignificant lower mucositis scores from controls on days 14 (P = 0.013),22 (P = 0.047) and 28 (P = 0.012), and had a significant reduction inthe number of animals days with a score of 3 or higher (P = 0.020). 4.The group treated with M40403 at 30 mg/kg/dose twice daily from day −1to day 3 had significantly lower scores than the control group on day 24(P = 0.048) and had a significant reduction in the number of animalsdays with a score of 3 or higher (P = 0.007). 5. The group treated withM40403 at 30 mg/kg/dose twice daily from day 0 to day 3 (group 7) hadsignificantly lower scores than the control group on days 14 (P <0.001), 16 (P = 0.001), 18 (P = 0.007), 20 (P = 0.001), 22 (P < 0.001),24 (P = 0.006), 26 (P = 0.001) and 28 (P = 0.012) and had a significantreduction in the number of animals days with a score of 3 or higher(P<0.001). 6. The group treated with M40403 at 30 mg/kg/dose twice dailyon day 0 (group 8) had significantly lower scores than the control groupon days 16 (P = 0.001), 18 (P = 0.033), 20 (P = 0.002), 22 (P < 0.001),24 (P = 0.010), 26 (P < 0.001) and 28 (P = 0.009) and had a significantreduction in the number of animals days with a score of 3 or higher (P <0.001). 7. The group treated with M40403 at 30 mg/kg/dose twice daily onday 0 and on day 7 had significantly lower scores than the control groupon days 14 (P = 0.004), 16 (P = 0.047), 20 (P < 0.001), 22 (P = 0.015)and 26 (P = 0.047) and had a significant reduction in the number ofanimals days with a score of 3 or higher (P < 0.001).

Other Embodiments

The detailed description set-forth above is provided to aid thoseskilled in the art in practicing the present invention. However, theinvention described and claimed herein is not to be limited in scope bythe specific embodiments herein disclosed because these embodiments areintended as illustration of several aspects of the invention. Anyequivalent embodiments are intended to be within the scope of thisinvention. Indeed, various modifications of the invention in addition tothose shown and described herein will become apparent to those skilledin the art from the foregoing description which do not depart from thespirit or scope of the present inventive discovery. Such modificationsare also intended to fall within the scope of the appended claims.

REFERENCES CITED

All publications, patents, patent applications and other referencescited in this application are incorporated herein by reference in theirentirety for all purposes to the same extent as if each individualpublication, patent, patent application or other reference wasspecifically and individually indicated to be incorporated by referencein its entirety for all purposes. Citation of a reference herein shallnot be construed as an admission that such is prior art to the presentinvention.

-   1. Knox J J, Puodziunas A L, Feld R. Chemotherapy-induced oral    mucositis. Prevention and management. Drugs Aging 2000;    17(4):257-67.-   2. Peterson D E. Research advances in oral mucositis. Curr Opin    Oncol 1999; 11(4):261-6.-   3. Plevova P. Prevention and treatment of chemotherapy- and    radiotherapy-induced oral mucositis: a review. Oral Oncol 1999;    35(5):453-70.-   4. Sonis S T, Oster G, Fuchs H, Bellm L, Bradford W Z, Edelsberg J,    et al. Oral mucositis and the clinical and economic outcomes of    hematopoietic stem-cell transplantation. J Clin Oncol 2001;    19(8):2201-5.-   5. Eldor A, Fuks Z, Matzner Y, Witte L D, Vlodavsky I. Perturbation    of endothelial functions by ionizing irradiation: effects on    prostaglandins, chemoattractants and mitogens. Semin Thromb Hemost    1989; 15(2):215-25.-   6. Sonis S T, Van Vugt A G, McDonald J, Dotoli E, Schwertschlag U,    Szklut P, et al. Mitigating effects of interleukin 11 on consecutive    courses of 5-fluorouracil-induced ulcerative mucositis in hamsters.    Cytokine 1997; 9(8):605-12.-   7. Sonis S T, Van Vugt A G, Brien J P, Muska A D, Bruskin A M, Rose    A, et al. Transforming growth factor-beta 3 mediated modulation of    cell cycling and attenuation of 5-fluorouracil induced oral    mucositis. Oral Oncol 1997; 33(1):47-54.-   8. Sonis S T, Peterson R L, Edwards L J, Lucey C A, Wang L, Mason L,    et al. Defining mechanisms of action of interleukin-11 on the    progression of radiation-induced oral mucositis in hamsters. Oral    Oncol 2000; 36(4):373-81.-   9. Sonis S T, Tracey C, Shklar G, Jenson J, Florine D. An animal    model for mucositis induced by cancer chemotherapy. Oral Surg Oral    Med Oral Pathol 1990; 69(4):437-448

APPENDICES

APPENDIX 1 Animal Weights DAY Group Animal −1 0 1 2 3 4 5 6 7 8 9 10 1112 13 Animal weights from a first study 1 1 69 92 92 90 101 102 107 110113 110 118 119 121 110 120 1 2 94 101 101 108 109 109 116 116 118 122121 125 126 123 134 1 3 93 96 96 99 102 106 107 104 112 115 115 118 120118 118 1 4 88 92 90 93 96 98 99 101 102 108 108 109 110 132 114 1 5 9698 98 102 106 109 113 108 117 123 123 127 129 130 130 1 6 97 102 101 107109 111 116 118 121 123 125 127 130 131 130 1 7 87 95 90 94 97 98 105104 101 105 105 105 107 110 109 1 8 91 96 97 100 102 103 105 109 111 115115 117 119 126 126 2 9 100 dead 2 10 91 93 90 95 91 93 92 99 101 106107 107 108 114 115 2 11 89 89 87 88 83 86 86 91 93 96 99 103 105 110111 2 12 98 99 98 109 106 108 116 117 121 103 123 125 126 125 130 2 1398 104 102 108 109 110 118 120 123 126 127 129 132 145 139 2 14 101 10298 98 97 98 106 110 112 117 119 120 122 128 128 2 15 76 76 75 74 77 7981 82 84 86 86 88 89 92 93 2 16 90 dead 3 17 93 99 98 98 99 103 105 103106 108 107 111 113 116 116 3 18 94 95 96 97 98 100 103 107 106 109 107108 108 115 116 3 19 98 98 100 101 105 107 109 118 114 115 113 116 119121 121 3 20 99 99 102 97 106 105 113 117 120 124 123 125 127 134 134 321 91 93 95 104 99 102 105 107 110 115 113 113 115 120 123 3 22 105 10495 110 112 115 120 124 128 132 130 136 138 144 145 3 23 92 93 93 97 99102 103 104 106 107 110 112 116 114 117 3 24 93 91 93 90 96 99 101 105107 109 107 107 110 101 105 4 25 96 97 95 93 96 98 102 106 107 110 111113 115 119 118 4 26 89 89 88 90 93 92 97 99 101 104 103 102 103 110 1064 27 93 98 93 98 102 105 106 107 109 116 118 119 120 123 119 4 28 99 10099 98 100 103 106 110 112 115 118 121 122 122 125 4 29 90 91 90 96 100102 100 101 104 107 107 108 110 112 111 4 30 93 98 95 99 102 103 106 111111 116 116 119 121 125 122 4 31 93 94 89 91 95 98 99 103 105 108 109112 115 116 114 4 32 91 92 91 95 98 100 102 102 105 109 111 112 114 114116 5 33 74 dead 5 34 85 83 84 83 86 88 87 90 94 97 98 100 102 106 106 535 96 96 96 100 101 102 100 103 108 111 116 115 116 119 118 5 36 90 9291 94 97 98 95 96 101 104 105 107 109 114 113 5 37 100 dead 5 38 96 101100 96 101 103 104 108 110 114 117 119 120 126 129 5 39 87 84 82 79 7879 81 84 86 91 93 94 99 97 98 5 40 69 82 79 78 79 82 81 86 87 91 94 96100 101 102 6 41 94 92 96 97 99 102 98 98 103 108 109 110 112 116 115 642 94 95 93 98 99 101 104 103 109 111 113 114 116 119 119 6 43 101 101101 107 109 110 115 117 122 126 127 129 130 134 134 6 44 90 dead 6 45 8986 88 90 91 96 94 92 95 99 102 102 105 105 102 6 46 93 94 92 103 102 102102 104 106 110 112 114 116 119 119 6 47 99 101 98 97 106 109 111 111119 118 119 123 126 125 126 6 48 91 dead 7 49 91 94 91 95 101 104 98 102106 107 108 113 115 119 120 7 50 93 95 92 91 93 93 98 104 103 105 106109 111 115 116 7 51 90 87 86 87 97 98 95 95 99 101 103 107 108 113 1137 52 95 99 95 99 102 104 107 108 113 115 114 113 115 120 120 7 53 92 9388 89 91 93 90 93 97 99 101 102 106 109 108 7 54 98 101 98 102 105 108101 106 109 112 113 116 119 121 122 7 55 91 93 90 93 99 101 98 101 104108 109 111 113 117 118 7 56 88 87 61 83 78 81 78 80 82 85 86 92 95 9499 8 57 94 97 93 99 102 105 105 108 112 113 114 117 119 120 121 8 58 8890 84 89 93 95 98 104 105 106 107 111 114 116 118 8 59 88 92 84 91 93 9797 100 102 105 103 105 108 110 112 8 60 86 89 88 96 95 96 99 100 105 106106 108 111 114 114 8 61 94 94 91 97 99 103 103 106 110 113 116 117 119125 124 8 62 93 94 88 93 98 101 104 108 111 108 112 118 120 122 121 8 6391 94 91 96 99 100 103 105 109 110 113 115 117 118 120 8 64 98 101 96101 107 107 111 113 117 118 119 125 127 124 124 9 65 98 101 100 104 108110 113 115 116 114 117 119 131 124 124 9 66 94 98 94 98 102 105 107 110112 113 114 117 118 125 124 9 67 89 93 90 95 98 101 104 106 108 105 109112 116 115 116 9 68 93 96 91 95 100 103 105 104 111 109 112 113 116 117116 9 69 98 99 98 102 106 109 110 114 118 119 121 124 129 131 129 9 7092 dead 9 71 91 92 89 94 96 100 102 105 106 104 107 110 111 116 120 9 7295 96 95 98 101 105 106 109 111 111 114 114 116 116 120 Animal weightsfrom a second study 1 1 88 92 91 94 96 98 102 103 103 106 108 110 114113 116 1 2 89 93 92 96 100 102 103 107 109 110 114 116 119 117 120 1 396 98 96 101 105 108 110 112 115 120 122 125 126 125 123 1 4 95 97 97102 103 107 108 111 114 117 116 121 125 123 126 1 5 88 91 88 91 94 97 98100 103 105 106 110 112 109 111 1 6 90 95 93 98 101 104 107 108 111 114115 122 122 121 124 1 7 85 89 88 91 94 96 92 99 103 102 104 108 110 108111 1 8 92 AOD 2 9 85 86 66 90 93 96 95 110 104 107 109 111 113 112 1132 10 88 89 66 91 94 96 97 100 104 106 107 108 112 112 114 2 11 68 91 9194 96 97 98 103 104 105 107 109 112 112 115 2 12 100 104 102 106 105 112113 116 121 121 124 129 132 129 132 2 13 77 51 80 84 87 53 94 95 97 96101 104 107 106 105 2 14 92 93 96 101 103 106 108 112 111 115 116 117118 117 120 2 15 63 91 69 93 95 95 97 101 102 104 106 109 111 113 115 216 94 97 97 100 102 105 106 113 112 115 116 120 123 123 126 3 17 90 9990 95 97 95 90 90 99 90 97 101 100 90 99 3 18 68 91 86 69 92 94 94 94 9899 96 97 93 91 93 3 19 90 93 90 90 92 94 82 80 84 84 85 82 87 dead 3 2068 91 85 69 82 84 88 79 81 80 78 80 81 80 82 3 21 101 102 98 100 101 103101 101 107 108 104 107 108 103 106 3 22 92 96 87 93 92 95 94 88 91 8682 83 80 78 80 3 23 65 dead 3 24 92 95 91 95 97 99 99 100 104 103 100101 100 98 100 4 25 86 90 88 91 93 95 99 97 102 105 103 109 105 110 1144 26 92 96 93 99 102 103 108 109 112 113 113 121 120 119 123 4 27 85 8786 89 90 94 94 98 99 102 119 97 107 105 108 4 28 94 96 96 101 103 106107 111 113 115 119 120 127 125 127 4 29 94 96 96 99 101 104 107 110 112117 117 123 122 121 123 4 30 91 94 95 99 102 104 104 100 109 113 115 117119 116 119 4 31 93 85 84 88 89 93 94 99 97 98 100 105 105 104 106 4 3274 74 75 79 79 82 86 87 92 94 95 103 98 95 98 5 33 83 83 83 89 89 98 9598 101 104 105 115 110 108 111 5 34 79 80 79 83 86 88 90 93 95 102 99101 104 103 106 5 35 83 87 85 90 93 95 97 94 101 102 103 105 106 105 1095 36 84 86 86 91 93 97 100 102 107 111 110 109 115 118 114 5 37 85 86 8588 89 91 93 102 99 101 102 106 108 107 111 5 38 78 79 79 82 84 83 88 9795 101 99 103 105 102 104 5 39 85 87 87 90 94 94 99 101 104 106 107 111112 111 113 5 40 81 83 82 87 89 90 93 95 97 100 101 107 107 107 109 6 4188 87 81 85 93 97 78 82 85 89 91 96 98 100 102 6 42 91 93 88 93 95 99102 107 112 114 115 120 122 120 123 6 43 84 87 84 83 79 78 84 93 69 9395 98 102 103 107 6 44 91 94 92 92 93 94 96 101 104 106 103 113 114 114119 6 45 78 dead 6 46 86 89 dead 6 47 89 93 86 91 79 91 92 99 101 105109 112 114 114 116 6 48 88 92 87 89 92 86 90 97 100 109 105 111 114 114118 DAY Group Animal 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Animalweights from a first study 1 1 120 120 130 132 133 137 138 139 143 140144 140 149 100 148 1 2 134 134 138 140 144 148 151 151 156 156 158 160162 162 164 1 3 119 123 124 127 130 131 129 133 135 137 139 142 144 142138 1 4 115 118 117 121 124 126 134 129 132 133 132 133 136 136 139 1 5133 135 138 141 142 148 147 150 153 154 158 165 163 163 159 1 6 131 131136 138 141 141 142 143 146 149 149 152 153 171 157 1 7 111 112 116 116120 121 122 123 127 128 128 130 134 128 136 1 8 129 130 130 132 137 137140 141 145 147 148 150 153 154 154 2 9 2 10 116 116 119 121 121 122 124125 127 129 132 137 133 135 135 2 11 112 113 118 120 121 124 126 127 133131 136 160 140 142 143 2 12 131 133 135 138 142 147 149 151 155 156 158134 165 164 168 2 13 140 142 144 147 149 154 150 156 160 162 165 166 166166 174 2 14 129 129 132 135 125 138 139 140 144 145 146 150 151 152 1552 15 99 95 99 101 101 103 105 106 109 111 109 110 114 115 116 2 16 3 17117 118 119 121 124 124 126 127 129 130 132 133 136 138 139 3 18 116 118120 123 125 128 130 132 138 138 140 142 145 148 148 3 19 122 125 128 131132 135 137 138 140 143 143 140 147 149 151 3 20 132 134 138 140 143 145146 149 152 154 156 160 160 162 165 3 21 123 125 127 129 132 132 134 136138 142 143 144 148 147 148 3 22 149 150 156 158 160 164 168 169 172 174176 179 181 183 182 3 23 117 116 117 120 120 126 126 128 130 131 132 136136 139 140 3 24 105 110 112 115 117 118 124 126 129 132 134 137 138 138143 4 25 121 124 128 130 131 132 133 134 137 139 140 142 145 145 144 426 109 110 112 117 111 117 119 119 121 128 125 126 127 130 128 4 27 123124 128 131 130 135 138 137 143 145 145 146 150 156 152 4 28 128 129 133135 137 139 140 140 144 145 148 150 152 151 152 4 29 117 119 121 124 125129 131 128 133 134 136 140 141 140 142 4 30 121 126 131 134 134 138 141141 145 148 149 152 154 158 157 4 31 117 120 123 125 128 127 131 130 132132 134 136 138 130 139 4 32 118 120 125 128 127 130 133 134 137 138 141143 145 133 148 5 33 5 34 107 108 109 111 120 118 120 120 126 129 128130 134 134 134 5 35 120 119 123 125 129 129 130 129 134 137 137 139 140141 142 5 36 116 117 119 121 120 125 127 127 131 133 133 135 139 134 1405 37 5 38 134 134 138 140 152 144 146 144 149 152 154 156 159 161 161 539 100 103 106 108 117 113 116 115 121 122 123 124 130 132 130 5 40 104103 104 105 116 113 112 111 115 117 118 119 125 128 124 6 41 114 116 117119 129 125 127 128 136 134 136 140 142 151 144 6 42 120 121 124 127 133132 133 133 141 140 142 143 146 149 150 6 43 135 138 141 142 150 150 154155 160 160 164 165 172 172 172 6 44 6 45 101 98 100 103 105 104 106 106111 111 111 113 115 114 115 6 46 122 123 126 128 132 131 134 132 138 139141 145 146 159 144 6 47 130 131 135 137 138 140 143 142 147 150 152 153156 141 160 6 48 7 49 127 130 131 133 135 140 141 142 148 149 150 152158 156 158 7 50 118 117 124 127 120 128 129 129 135 137 138 140 143 142146 7 51 118 121 118 121 126 127 133 131 137 138 138 140 144 146 145 752 124 122 128 131 132 133 137 136 143 142 143 145 148 140 149 7 53 110112 117 120 118 121 124 124 128 129 130 133 135 138 137 7 54 125 126 129129 135 137 138 138 142 144 146 147 151 145 152 7 55 120 123 125 127 130130 132 133 139 140 142 145 148 146 150 7 56 100 102 105 108 111 112 113113 116 121 123 124 127 121 130 8 57 123 125 128 131 138 132 137 137 139140 143 143 147 147 148 8 58 119 120 120 124 128 128 131 131 134 134 135137 139 135 142 8 59 111 115 118 121 122 118 122 121 123 126 127 131 129126 127 8 60 117 118 122 124 125 128 131 131 136 138 139 143 145 146 1468 61 126 128 126 130 138 137 139 141 142 144 144 146 151 151 153 8 62122 126 128 130 134 133 137 138 138 142 145 147 147 154 153 8 63 123 125127 131 129 132 135 135 137 138 139 147 143 145 146 8 64 125 126 127 130131 135 137 135 139 142 142 144 147 142 151 9 65 127 126 133 137 135 136138 139 141 142 144 146 149 148 151 9 66 127 129 130 134 137 139 141 139143 145 148 150 152 144 152 9 67 119 118 123 126 126 128 130 130 132 135136 137 140 128 143 9 68 120 119 121 124 129 127 130 129 131 122 133 136134 122 136 9 69 133 134 138 141 142 146 152 149 151 153 155 159 162 165166 9 70 9 71 122 122 125 128 128 131 143 134 137 139 139 141 145 142147 9 72 120 120 121 124 133 128 129 125 129 132 154 137 138 138 140Animal weights from a second study 1 1 115 115 117 119 119 114 115 116117 118 121 122 123 124 127 1 2 124 124 125 129 131 131 135 136 136 138140 141 147 149 148 1 3 131 132 137 142 145 144 148 152 153 155 159 161161 163 169 1 4 124 123 124 129 130 131 134 138 139 140 143 147 145 149152 1 5 111 112 113 117 119 119 123 127 127 128 131 132 133 136 136 1 6127 125 124 128 130 130 134 136 139 141 128 147 148 149 153 1 7 113 112114 116 117 118 123 123 124 125 145 128 139 133 134 1 8 2 9 116 115 121123 125 127 133 135 138 139 142 144 146 149 152 2 10 118 117 118 121 123125 129 130 132 135 139 142 143 147 146 2 11 119 116 117 119 120 121 125126 128 129 131 134 134 138 139 2 12 134 135 135 138 142 140 145 144 150150 154 155 156 162 160 2 13 112 111 113 117 119 117 122 125 124 122 129130 132 136 136 2 14 118 120 122 123 127 128 131 134 135 136 140 144 142144 150 2 15 118 120 121 123 124 126 129 131 132 135 135 137 138 140 1422 16 127 126 128 129 131 131 135 136 136 140 143 145 143 113 151 3 17 9997 94 90 102 102 100 110 115 117 121 124 124 127 131 3 18 91 86 84 64 8391 95 99 101 104 108 111 112 115 118 3 19 3 20 83 78 77 79 81 85 89 9397 99 103 99 108 110 115 3 21 103 99 99 98 106 107 112 115 119 117 127128 129 132 135 3 22 79 74 72 75 79 81 85 88 91 93 97 106 107 108 109 323 3 24 102 99 101 105 108 110 114 117 121 123 127 130 132 135 138 4 25115 116 119 124 125 123 129 131 133 133 137 138 140 145 146 4 26 123 124129 134 134 133 141 144 145 143 150 151 152 156 160 4 27 110 110 111 114116 114 118 121 123 124 126 130 131 133 136 4 28 129 127 129 132 132 135138 142 143 143 128 148 158 148 154 4 29 125 125 130 132 138 135 142 142145 149 151 153 157 160 161 4 30 122 120 126 127 130 127 134 136 139 139142 142 144 146 149 4 31 111 109 112 114 116 117 120 123 124 122 129 130130 133 135 4 32 107 104 108 111 112 112 116 119 122 126 125 125 124 126132 5 33 112 111 114 118 119 120 124 124 124 128 131 132 138 141 140 534 111 110 114 118 119 121 123 127 126 128 132 133 134 137 139 5 35 120113 114 116 116 119 124 126 125 128 130 132 137 134 138 5 36 120 121 124127 130 132 135 137 139 144 145 148 150 152 156 5 37 110 108 111 115 117116 121 123 124 124 129 129 131 134 136 5 38 107 108 110 114 117 116 122125 125 128 131 134 133 137 139 5 39 113 118 121 125 125 127 130 132 132134 136 137 146 142 148 5 40 112 110 113 116 118 118 121 123 124 125 128128 130 133 135 6 41 106 107 110 112 116 117 120 121 123 125 128 128 130136 136 6 42 118 117 115 108 106 104 104 103 104 104 106 108 108 109 1106 43 109 108 112 115 115 116 122 124 124 125 127 130 129 131 134 6 44120 120 123 125 127 128 132 133 135 137 137 138 136 139 142 6 45 6 46 647 124 124 127 129 133 133 137 137 136 138 141 143 142 150 146 6 48 122122 126 129 129 131 135 137 138 139 142 145 143 146 149

APPENDIX 2 Mucositis Scores Cheek pouch photographs were scored by 2independent scores in a blinded manner resulting in 2 scores for eachanimal at each time point. DAY Group Animal 6 8 10 12 14 16 18 20 22 2426 28 ACT-03 Blinded Scores Mucositis scores from a first study 1 1 0 00 2 3 3 3 3 3 2 2 1 1 1 0 0 0 1 3 3 3 3 3 2 1 1 1 2 1 0 1 2 3 3 4 3 3 32 2 1 2 0 0 0 2 3 3 3 3 3 3 2 1 1 3 1 0 1 2 3 4 3 3 3 2 2 2 1 3 0 0 0 13 4 3 3 3 1 2 1 1 4 1 0 0 2 3 3 3 4 2 2 2 2 1 4 0 0 0 1 3 3 3 3 2 2 2 11 5 0 1 0 2 3 3 3 3 3 2 2 2 1 5 0 0 1 2 3 3 3 3 3 1 1 1 1 6 0 0 1 2 3 34 3 2 2 2 2 1 6 0 0 1 2 3 3 3 3 2 2 2 1 1 7 0 0 1 2 3 3 2 2 1 1 1 1 1 70 0 1 2 3 3 1 1 1 1 1 1 1 8 1 0 1 1 2 3 3 3 3 2 2 2 1 8 0 0 1 0 2 3 3 33 2 2 1 2 9 dead 2 9 2 10 0 0 1 2 2 3 2 2 1 1 1 1 2 10 0 0 1 1 2 3 2 2 11 1 1 2 11 0 0 1 2 3 3 3 3 3 2 1 1 2 11 0 0 0 1 3 3 3 3 3 2 2 2 2 12 0 01 1 3 3 3 3 2 2 2 1 2 12 0 0 0 1 3 3 3 3 2 1 2 1 2 13 0 0 1 2 3 3 3 3 32 2 1 2 13 0 1 0 2 3 3 3 3 3 2 2 1 2 14 0 0 1 2 2 3 3 3 2 2 1 0 2 14 1 10 1 2 3 3 3 2 2 2 1 2 15 0 0 1 2 2 2 2 2 2 1 1 1 2 15 0 0 0 1 2 2 2 2 21 1 2 2 16 dead 2 16 3 17 0 0 1 1 1 3 3 3 2 2 1 0 3 17 1 0 1 1 2 3 3 3 22 2 1 3 18 0 0 1 1 2 3 3 3 3 3 2 0 3 18 1 1 1 1 2 3 3 3 3 3 2 1 3 19 0 01 2 3 3 3 3 2 2 2 0 3 19 1 1 0 2 3 3 3 3 2 2 1 2 3 20 0 0 1 1 2 3 4 3 21 2 1 3 20 0 0 1 2 2 3 3 3 2 1 1 2 3 21 0 0 0 1 2 2 2 2 2 1 2 0 3 21 0 00 1 2 2 2 2 2 2 2 1 3 22 0 0 1 2 1 2 2 2 1 1 1 0 3 22 0 1 0 1 2 2 2 2 22 1 1 3 23 0 0 0 3 3 4 4 3 2 2 2 0 3 23 0 1 0 3 3 4 4 3 2 2 1 1 3 24 0 01 2 3 3 3 3 2 1 2 0 3 24 1 1 0 2 3 3 3 3 2 1 1 1 4 25 0 0 1 2 1 1 1 1 11 2 1 4 25 0 0 0 2 1 1 1 1 2 2 1 2 4 26 0 0 0 0 3 3 3 3 2 1 2 1 4 26 0 00 0 3 3 3 3 2 2 1 2 4 27 0 0 1 2 2 3 3 3 3 2 2 0 4 27 0 1 0 2 2 4 3 3 32 2 1 4 28 0 0 2 2 3 3 3 3 3 2 2 1 4 28 0 0 2 2 3 3 3 3 3 2 2 2 4 29 0 01 2 3 3 4 3 2 2 2 0 4 29 0 0 0 1 3 4 3 3 2 2 1 1 4 30 0 0 1 2 3 3 3 3 22 2 0 4 30 0 0 0 1 3 4 3 3 2 2 2 2 4 31 0 0 1 2 3 3 2 2 2 2 2 1 4 31 0 00 2 3 3 2 2 2 2 1 2 4 32 0 0 1 2 3 3 3 3 3 2 2 1 4 32 0 0 0 2 3 4 3 3 32 1 2 5 33 dead 5 33 5 34 0 0 0 2 3 3 3 2 2 1 1 0 5 34 0 0 0 2 3 3 3 2 22 1 1 5 35 0 0 1 2 3 3 3 3 2 2 2 1 5 35 0 0 0 2 3 4 3 3 2 2 1 2 5 36 0 01 2 2 2 2 2 0 1 1 1 5 36 0 0 0 1 2 2 2 2 1 1 0 2 5 37 dead 5 37 5 38 0 00 2 2 2 2 2 2 0 2 0 5 38 1 0 0 1 2 2 1 2 1 0 1 1 5 39 0 0 0 1 3 3 3 3 31 1 0 5 39 0 1 0 0 3 3 3 3 3 0 1 1 5 40 1 0 2 1 2 3 3 3 3 2 2 0 5 40 0 11 1 2 3 3 3 3 2 2 1 6 41 0 0 1 1 3 3 3 3 3 2 2 0 6 41 1 0 1 0 3 3 3 3 32 2 1 6 42 0 0 1 2 3 3 3 4 2 2 2 1 6 42 0 0 1 1 3 3 3 3 2 2 1 2 6 43 0 00 2 3 3 2 2 2 2 2 1 6 43 1 0 0 2 3 3 2 2 2 1 2 2 6 44 dead 6 44 6 45 0 01 2 2 4 4 4 4 4 3 2 6 45 1 0 0 2 2 4 4 4 4 4 3 2 6 46 0 0 0 2 3 3 3 3 22 2 0 6 46 0 0 0 2 3 3 3 3 2 2 2 1 6 47 0 0 1 2 2 3 2 2 0 2 2 2 6 47 0 10 0 2 3 2 2 1 2 1 1 6 48 dead 6 48 7 49 0 0 1 2 2 1 1 1 0 1 1 1 7 49 0 10 2 2 1 0 0 1 0 1 1 7 50 0 0 0 2 2 2 3 1 1 0 0 0 7 50 1 0 0 2 2 1 3 0 21 1 1 7 51 0 0 1 1 2 3 1 2 1 0 0 0 7 51 1 0 0 0 2 3 2 1 2 0 1 1 7 52 0 00 2 2 2 2 2 1 0 0 0 7 52 1 1 0 2 2 2 1 0 2 1 1 1 7 53 0 0 1 1 2 3 3 3 21 1 0 7 53 0 1 0 0 2 3 3 3 2 2 1 1 7 54 0 0 2 2 2 3 3 3 2 0 1 0 7 54 0 00 2 2 3 3 3 1 2 1 2 7 55 0 0 0 2 3 2 2 2 2 1 2 0 7 55 0 0 0 2 3 2 2 1 22 1 2 7 56 0 0 1 2 2 2 1 1 1 2 2 0 7 56 0 0 1 1 2 2 1 1 1 2 1 1 8 57 0 00 2 3 3 3 3 1 1 0 1 8 57 0 1 0 2 3 3 3 3 1 2 0 2 8 58 1 0 0 2 2 2 2 2 11 1 1 8 58 1 0 0 2 2 2 2 2 1 2 0 1 8 59 0 0 1 2 1 1 1 1 1 1 2 0 8 59 1 00 2 1 2 1 2 1 1 2 1 8 60 0 0 1 1 3 3 3 1 1 0 0 0 8 60 0 0 0 1 3 3 3 2 12 0 1 8 61 0 0 1 2 2 2 3 2 1 1 1 0 8 61 0 0 0 2 2 2 3 1 1 1 1 1 8 62 0 00 2 3 2 1 2 2 0 1 0 8 62 0 0 0 1 3 2 2 1 2 2 0 1 8 63 0 0 1 2 2 2 1 2 20 1 0 8 63 1 0 1 2 2 2 1 1 2 2 0 1 8 64 0 0 1 2 3 3 3 3 2 0 2 0 8 64 1 00 2 3 3 3 3 2 1 0 1 9 65 0 0 1 2 2 3 3 2 2 0 2 1 9 65 1 0 0 2 2 3 3 2 21 1 2 9 66 0 0 0 2 2 2 2 2 0 1 1 0 9 66 1 0 0 1 1 1 1 1 1 2 0 1 9 67 0 00 2 1 1 2 1 0 0 1 0 9 67 1 0 0 1 1 1 1 1 1 1 0 1 9 68 1 1 2 2 2 3 3 2 11 2 0 9 68 1 0 0 1 2 3 3 1 2 2 1 1 9 69 0 0 0 2 3 3 3 3 3 3 2 1 9 69 1 10 1 3 3 3 3 3 3 1 2 9 70 9 70 9 71 0 0 1 2 2 2 2 2 2 1 2 0 9 71 0 0 0 22 2 2 2 2 2 1 2 9 72 0 0 0 2 3 4 3 1 2 2 2 1 9 72 0 0 0 2 3 3 3 2 2 1 12 ACT-02 Blinded Scores Mucositis scores from a second study 1 1 0 1 1 22 2 2 2 2 1 0 0 1 1 0 1 1 2 2 2 2 2 2 1 0 0 1 2 0 1 1 2 3 3 2 2 2 2 2 11 2 0 1 1 2 3 3 2 2 2 2 2 1 1 3 0 1 1 2 3 3 3 3 3 2 2 2 1 3 0 1 1 2 3 33 3 3 2 2 2 1 4 0 1 1 2 3 3 3 3 3 2 2 1 1 4 0 1 1 2 3 3 3 3 3 2 2 1 1 50 1 2 2 3 3 3 3 3 2 2 1 1 5 0 1 2 2 3 3 3 3 3 2 2 1 1 6 0 0 1 2 3 3 3 33 3 2 2 1 6 0 0 1 2 3 3 3 3 3 3 2 2 1 7 1 1 1 1 2 3 3 3 2 2 2 1 1 7 1 11 1 2 3 3 3 2 2 2 1 1 8 1 8 2 9 0 1 1 2 3 3 3 3 2 2 2 2 2 9 0 1 1 2 3 33 3 2 2 2 2 2 10 1 0 1 2 3 3 3 3 3 2 2 2 2 10 1 0 1 2 3 3 3 3 3 2 2 2 211 0 1 1 1 3 3 3 3 3 3 2 2 2 11 0 1 1 1 3 3 3 3 3 3 2 2 2 12 1 1 1 2 3 33 3 3 3 2 1 2 12 1 1 1 2 3 3 3 3 3 3 2 1 2 13 1 1 1 1 3 3 3 3 2 2 3 2 213 0 1 1 1 3 3 3 3 2 2 3 2 2 14 0 1 2 2 3 3 3 3 2 2 2 1 2 14 0 1 2 2 3 33 3 2 2 2 1 2 15 1 1 1 1 1 2 2 1 2 2 2 2 2 15 0 1 1 1 1 2 2 1 2 2 2 2 216 1 0 1 2 2 2 3 3 3 2 1 1 2 16 1 0 1 2 2 2 3 3 3 2 1 1 3 17 0 1 1 2 2 33 3 3 3 2 2 3 17 0 1 1 2 2 3 3 3 3 3 2 2 3 18 1 1 1 2 3 3 3 3 3 3 1 1 318 1 1 1 2 3 3 3 3 3 3 1 1 3 19 1 1 1 1 3 19 1 1 1 1 3 20 1 1 1 1 3 3 33 3 3 3 2 3 20 1 1 1 1 3 3 3 3 3 3 3 2 3 21 0 1 1 1 3 3 3 3 3 3 2 2 3 210 1 1 1 3 3 3 3 3 3 2 2 3 22 1 1 2 2 3 3 3 3 2 2 2 1 3 22 1 1 2 2 3 3 33 2 2 2 1 3 23 3 23 3 24 0 0 1 1 2 2 3 2 2 1 1 1 3 24 0 0 1 1 2 2 3 2 21 1 1

What is claimed is:
 1. A method of treating an oral mucositis in asubject, the method comprising administering a superoxide dismutasemimetic to a subject in need thereof.
 2. A method of treating an oralmucositis in accordance with claim 1, wherein the administering lessensthe severity of the oral mucositis in a subject.
 3. A method of treatingan oral mucositis in accordance with claim 1, wherein the superoxidedismutase mimetic is a compound represented by the formula:

wherein R₁, R′₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇, R′₇,R₈, R′₈, R₉, R′₉, R₁₀, and R′₁₀ are each independently selected from thegroup consisting of hydrogen, alkenyl, alkenylcycloalkenyl,alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl,aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylcycloalkyl, cycloalkenylalkyl, and heterocyclyl, and aralkylradicals and radicals attached to the α-carbon or α-amino acids, and—OR₁₁, —NR₁₁R₁₂, —COR₁₁, —CO₂R₁₁, —CONR₁₁R₁₂, —SR₁₁, —SOR₁₁, —SO₂R₁₁,—SO₂NR₁₁R₁₂, —N(OR₁₁)(R₁₂), —P(O)(OR₁₁)(OR₁₂), —P(O)(OR₁₁)(R₁₂),—OP(O)(OR₁₁)(OR₁₂), and substituents attached to the α-carbon of α-aminoacids, wherein R₁₁ and R₁₂ are independently hydrogen or alkyl; andoptionally, one or more of R₁ or R′₁ and R₂ or R′₂, R₃ or R′₃ and R₄ orR′₄, R₅ or R′₅ and R₆ or R′₆, R₇ or R′₇ and R₈ or R′₈, R₉ or R′₉ and R₁₀or R′₁₀ together with the carbon atoms to which they are attachedindependently form a substituted or unsubstituted and saturated,partially saturated, or unsaturated cycle or heterocycle having 3 to 20carbon atoms; and optionally, one or more of R₁ and R′₁, R₂ and R′₂, R₃and R′₃, R₄ and R′₄, R₅ and R′₅, R₆ and R′₆, R₇ and R′₇, R₈ and R′₈, R₉and R′₉, and R₁₀ and R′₁₀, together with the carbon atom to which theyare attached independently form a substituted or unsubstituted andsaturated, partially saturated, or unsaturated cycle or heterocyclehaving 3 to 20 carbon atoms; and optionally, one or more of R₁₀ or R′₁₀and R₁ or R′₁, R₂ or R′₂ and R₃ or R′₃, R₄ or R′₄ and R₅ or R′₅, R₆ orR′₆ and R₇ or R′₇, or R₈ or R′₈ and R₉ or R′₉ together with the carbonatoms to which they are attached independently form a substituted orunsubstituted nitrogen containing heterocycle having 3 to 20 carbonatoms, which may be an aromatic heterocycle in which case the hydrogenattached to the nitrogen which is both part of the heterocycle and themacrocycle and the R groups attached to the carbon atoms which are bothpart of the heterocycle and the macrocycle are absent; and optionally,one or more of R₁, R′₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇,R′₇, R₈, R′₈, R₉, R′₉, R₁₀, and R′₁₀, together with a different one ofR₁, R′₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇, R′₇, R₈, R′₈,R₉, R′₉, R₁₀, and R′₁₀, which is attached to a different carbon atom inthe macrocyclic ligand may be bound to form a strap represented by theformula:—(CH₂)_(I)-Q-(CH₂)_(J)—R—(CH₂)_(K)—S—(CH₂)_(L)— wherein I, J, K and Lindependently are integers from 0 to 10 and Q, R and S are independentlyselected from the group consisting of alkenyl, alkenylcycloalkenyl,alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl,aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylcycloalkyl, cycloalkenylalkyl, and heterocyclyl, aza, amide,ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl,phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate,urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza, andcombinations thereof; and combinations of any of the above; wherein M isa cation of a transition metal; and wherein X, Y and Z are independentlyselected from the group consisting of halide, oxo, aquo, hydroxo,alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo,ammonia, alkylamino, arylamino, heterocycloalkyl amino, heterocycloarylamino, amine oxides, hydrazine, alkyl hydrazine, aryl hydrazine, nitricoxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkylnitrile, aryl nitrile, alkyl isonitrile, aryl isonitrile, nitrate,nitrite, azido, alkyl sulfonic acid, aryl sulfonic acid, alkylsulfoxide, aryl sulfoxide, alkyl aryl sulfoxide, alkyl sulfenic acid,aryl sulfenic acid, alkyl sulfinic acid, aryl sulfinic acid, alkyl thiolcarboxylic acid, aryl thiol carboxylic acid, alkyl thiol thiocarboxylicacid, aryl thiol thiocarboxylic acid, alkyl carboxylic acid, arylcarboxylic acid, urea, alkyl urea, aryl urea, alkyl aryl urea, thiourea,alkyl thiourea, aryl thiourea, alkyl aryl thiourea, sulfate, sulfite,bisulfate, bisulfite, thiosulfate, thiosulfite, hydrosulfite, alkylphosphine, aryl phosphine, alkyl phosphine oxide, aryl phosphine oxide,alkyl aryl phosphine oxide, alkyl phosphine sulfide, aryl phosphinesulfide, alkyl aryl phosphine sulfide, alkyl phosphonic acid, arylphosphonic acid, alkyl phosphinic acid, aryl phosphinic acid, alkylphosphinous acid, aryl phosphinous acid, phosphate, thiophosphate,phosphite, pyrophosphite, triphosphate, hydrogen phosphate, dihydrogenphosphate, alkyl guanidino, aryl guanidino, alkyl aryl guanidino, alkylcarbamate, aryl carbamate, alkyl aryl carbamate, alkyl thiocarbamate,aryl thiocarbamate, alkylaryl thiocarbamate, alkyl dithiocarbamate, aryldithiocarbamate, alkylaryl dithiocarbamate, bicarbonate, carbonate,perchlorate, chlorate, chlorite, hypochlorite, perbromate, bromate,bromite, hypobromite, tetrahalomanganate, tetrafluoroborate,hexafluoroantimonate, hypophosphite, iodate, periodate, metaborate,tetraaryl borate, tetra alkyl borate, tartrate, salicylate, succinate,citrate, ascorbate, saccharinate, amino acid, hydroxamic acid,thiotosylate, and anions of ion exchange resins, or the correspondinganions thereof; or X, Y and Z are independently selected from the groupconsisting of charge-neutralizing anions which are derived from anymonodentate or polydentate coordinating ligand and a ligand system andthe corresponding anion thereof; or X, Y and Z are independentlyattached to one or more of R₁, R′₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅,R₆, R′₆, R₇, R′₇, R₈, R′₈, R₉, R′₉, R₁₀, and R′₁₀; and n is an integerfrom 0 to
 3. 4. A method in accordance with claim 3, wherein M isselected from the group consisting of Mn²⁺, Mn³⁺, Mn⁴⁺, Mn⁶⁺, Mn⁷⁺,Fe²⁺, Fe³⁺, Fe⁴⁺, Fe⁶⁺, Ni²⁺, Ni³⁺, Cu¹⁺, Cu²⁺, V²⁺, V³⁺, V⁴⁺, or V⁵⁺.5. A method in accordance with claim 3, wherein M is selected from thegroup consisting of Mn²⁺, Mn³⁺, Mn⁴⁺, Mn⁶⁺, Mn⁷⁺, Fe²⁺, Fe³⁺, Fe⁴⁺, andFe⁶⁺.
 6. A method in accordance with claim 3, wherein M is Mn².
 7. Amethod of treating an oral mucositis in accordance with claim 1, whereinthe superoxide dismutase mimetic is a compound represented by theformula.

wherein a nitrogen of the macrocycle and two adjacent carbon atoms towhich the nitrogen is attached independently form a substituted orunsubstituted, saturated, partially saturated or unsaturatednitrogen-containing heterocycle W having 2 to 20 carbon atoms, which maybe an aromatic heterocycle in which case the hydrogen attached to thenitrogen which is both part of the heterocycle and the macrocycle andthe R groups attached to the carbon atoms which are both part of theheterocycle and the macrocycle are absent; and wherein R₁, R′₁, R₂, R′₂,R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, Ry, R′₇, R₈, R′₈, R₉, R′₉, R₁₀, andR′₁₀ are each independently selected from the group consisting ofhydrogen, alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl,alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl,cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl,cycloalkenylalkyl, and heterocyclyl, and aralkyl radicals and radicalsattached to the α-carbon or α-amino acids, and —OR₁₁, —NR₁₁R₁₂, —COR₁₁,—CO₂R₁₁, —CONR₁₁R₁₂, —SR₁₁, —SOR₁₁, —SO₂R₁₁, —SO₂NR₁₁R₁₂, —N(OR₁₁)(R₁₂),—P(O)(OR₁₁)(OR₁₂), —P(O)(OR₁₁)(R₁₂), —OP(O)(OR₁₁)(OR₁₂), andsubstituents attached to the α-carbon of α-amino acids, wherein R11 andR₁₂ are independently hydrogen or alkyl; and, optionally, one or more ofR₁ and R₂ or R′₂, R₃ or R′₃ and R₄ or R′₄, R₅ or R′₅ and R₆ or R′₆, R₇or R′₇ and R₈ or R′₈, R₉ or R′₉ and R₁₀ together with the carbon atomsto which they are attached independently form a substituted orunsubstituted and saturated, partially saturated, or unsaturated cycleor heterocycle having 3 to 20 carbon atoms; and, optionally, one or moreof R₂ and R′₂, R₃ and R′₃, R₄ and R′₄, R₅ and R′₅, R₆ and R′₆, R₇ andR′₇, R₈ and R′8, and R₉ and R′₉, together with the carbon atom to whichthey are attached independently form a substituted or unsubstituted andsaturated, partially saturated, or unsaturated cycle or heterocyclehaving 3 to 20 carbon atoms; and, optionally, one or more of R₂ or R′₂and R₃ or R′₃, R₄ or R′₄ and R₅ or R′₅, R₆ or R′₆ and R₇ or R′₇, or R₈or R′₈ and R₉ or R′₉ together with the carbon atoms to which they areattached independently form a substituted or unsubstituted nitrogencontaining heterocycle having 3 to 20 carbon atoms, which may be anaromatic heterocycle in which case the hydrogen attached to the nitrogenwhich is both part of the heterocycle and the macrocycle and the Rgroups attached to the carbon atoms which are both part of theheterocycle and the macrocycle are absent; and, optionally, one or moreof R₁, R′₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇, R′₇, R₈,R′₈, R₉, R′₉, and R₁₀, together with a different one of R₁, R′₁, R₂,R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇, R′₇, R₈, R′₈, R₉, R′₉, andR₁₀, which is attached to a different carbon atom in the macrocyclicligand may be bound to form a strap represented by the formula:—(CH₂)_(I)-Q-(CH₂)_(J)—R—(CH₂)_(K)—S—(CH₂)_(L)— wherein I, J, K and Lindependently are integers from 0 to 10 and Q, R and S are independentlyselected from the group consisting of alkenyl, alkenylcycloalkenyl,alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl,aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylcycloalkyl, cycloalkenylalkyl, and heterocyclyl, aza, amide,ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl,phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate,urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza, andcombinations thereof; and optionally, one or more of R₁, R′₁, R₂, R′₂,R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇, R′₇, R₈, R′₈, R₉, R′₉, and R₁₀,may be bound to an atom of heterocycle W to form a strap represented bythe formula:—(CH₂)_(I)-Q-(CH₂)_(J)—R—(CH₂)_(K)—S—(CH₂)_(L)— wherein I, J, K and Lindependently are integers from 0 to 10 and Q, R and S are independentlyselected from the group consisting of alkenyl, alkenylcycloalkenyl,alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl,aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylcycloalkyl, cycloalkenylalkyl, and heterocyclyl, aza, amide,ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl,phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate,urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza, andcombinations thereof; and combinations of any of the above; wherein M isa cation of a transition metal; and wherein X, Y and Z are independentlyselected from the group consisting of halide, oxo, aquo, hydroxo,alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo,ammonia, alkylamino, arylamino, heterocycloalkyl amino, heterocycloarylamino, amine oxides, hydrazine, alkyl hydrazine, aryl hydrazine, nitricoxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkylnitrile, aryl nitrile, alkyl isonitrile, aryl isonitrile, nitrate,nitrite, azido, alkyl sulfonic acid, aryl sulfonic acid, alkylsulfoxide, aryl sulfoxide, alkyl aryl sulfoxide, alkyl sulfenic acid,aryl sulfenic acid, alkyl sulfinic acid, aryl sulfinic acid, alkyl thiolcarboxylic acid, aryl thiol carboxylic acid, alkyl thiol thiocarboxylicacid, aryl thiol thiocarboxylic acid, alkyl carboxylic acid, arylcarboxylic acid, urea, alkyl urea, aryl urea, alkyl aryl urea, thiourea,alkyl thiourea, aryl thiourea, alkyl aryl thiourea, sulfate, sulfite,bisulfate, bisulfite, thiosulfate, thiosulfite, hydrosulfite, alkylphosphine, aryl phosphine, alkyl phosphine oxide, aryl phosphine oxide,alkyl aryl phosphine oxide, alkyl phosphine sulfide, aryl phosphinesulfide, alkyl aryl phosphine sulfide, alkyl phosphonic acid, arylphosphonic acid, alkyl phosphinic acid, aryl phosphinic acid, alkylphosphinous acid, aryl phosphinous acid, phosphate, thiophosphate,phosphite, pyrophosphite, triphosphate, hydrogen phosphate, dihydrogenphosphate, alkyl guanidino, aryl guanidino, alkyl aryl guanidino, alkylcarbamate, aryl carbamate, alkyl aryl carbamate, alkyl thiocarbamate,aryl thiocarbamate, alkylaryl thiocarbamate, alkyl dithiocarbamate, aryldithiocarbamate, alkylaryl dithiocarbamate, bicarbonate, carbonate,perchlorate, chlorate, chlorite, hypochlorite, perbromate, bromate,bromite, hypobromite, tetrahalomanganate, tetrafluoroborate,hexafluoroantimonate, hypophosphite, iodate, periodate, metaborate,tetraaryl borate, tetra alkyl borate, tartrate, salicylate, succinate,citrate, ascorbate, saccharinate, amino acid, hydroxamic acid,thiotosylate, and anions of ion exchange resins, or the correspondinganions thereof; or X, Y and Z are independently selected from the groupconsisting of charge-neutralizing anions which are derived from anymonodentate or polydentate coordinating ligand and a ligand system andthe corresponding anion thereof; or X, Y and Z are independentlyattached to one or more of R₁, R′₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅,R₆, R′₆, R₇, R′₇, R₈, R′₈, R₉, R′₉, and R₁₀; and n is an integer from 0to
 3. 8. A method in accordance with claim 7, wherein M is selected fromthe group consisting of Mn²⁺, Mn³⁺, Mn⁴⁺, Mn⁶⁺, Mn⁷⁺, Fe²⁺, Fe³⁺, Fe⁴⁺,Fe⁶⁺, Ni²⁺, Ni³⁺, Cu¹⁺, Cu²⁺, V²⁺, V³⁺, V⁴⁺, and V⁵⁺.
 9. A method inaccordance with claim 7, wherein M is selected from the group consistingof Mn²⁺, Mn³⁺, Mn⁴⁺, Mn⁶⁺, Mn⁷⁺, Fe²⁺, Fe³⁺, Fe⁴⁺, and Fe⁶⁺.
 10. Amethod in accordance with claim 7, wherein M is Mn²⁺.
 11. A method inaccordance with claim 7, where W is a substituted or unsubstitutedpyridino moiety.
 12. A method of treating an oral mucositis inaccordance with claim 1, wherein the superoxide dismutase mimetic is acompound represented by the formula:

wherein a nitrogen of the macrocycle and two adjacent carbon atoms towhich the nitrogen is attached independently form a substituted orunsubstituted, saturated, partially saturated or unsaturatednitrogen-containing heterocycle W having 2 to 20 carbon atoms, which maybe an aromatic heterocycle in which case the hydrogen attached to thenitrogen which is both part of the heterocycle and the macrocycle andthe R groups attached to the carbon atoms which are both part of theheterocycle and the macrocycle are absent; and two sets of two adjacentcarbon atoms of the macrocycle independently form substituted orunsubstituted, saturated, partially saturated or unsaturated, cycles orheterocycles U and V having 3 to 20 carbon atoms; and wherein R₁, R′₁,R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇, R′₇, R₈, R′₈, R₉, R′₉,R₁₀, and R′₁₀ are each independently selected from the group consistingof hydrogen, alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl,alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl,cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl,cycloalkenylalkyl, and heterocyclyl, and aralkyl radicals and radicalsattached to the α-carbon or α-amino acids, and —OR₁₁, —NR₁₁R₁₂, —COR₁₁,—CO₂R₁₁, —CONR₁₁R₁₂, —SR₁₁, —SOR₁₁, —SO₂R₁₁, —SO₂NR₁₁R₁₂, —N(OR₁₁)(R₁₂),—P(O)(OR₁₁)(OR₁₂), —P(O)(OR₁₁)(R₁₂), —OP(O)(OR₁₁)(OR₁₂), andsubstituents attached to the α-carbon of α-amino acids, wherein R₁₁ andR₁₂ are independently hydrogen or alkyl; and, optionally, one or more ofR₁ and R₂ or R′₂, R₅ or R′₅ and R₆ or R′₆, R₉ or R′₉ and R₁₀ togetherwith the carbon atoms to which they are attached independently form asubstituted or unsubstituted and saturated, partially saturated, orunsaturated cycle or heterocycle having 3 to 20 carbon atoms; and,optionally, one or more of R₂ and R′₂, R₅ and R′₅, R₆ and R′₆, and R₉and R′₉, together with the carbon atom to which they are attachedindependently form a substituted or unsubstituted and saturated,partially saturated, or unsaturated cycle or heterocycle having 3 to 20carbon atoms; and, optionally, one or more of R₂ or R′₂ and R₃, R₄ andR₅ or R′₅, R₆ or R′₆ and R₇, or R₈ and R₉ or R′₉ together with thecarbon atoms to which they are attached independently form a substitutedor unsubstituted nitrogen containing heterocycle having 3 to 20 carbonatoms, which may be an aromatic heterocycle in which case the hydrogenattached to the nitrogen which is both part of the heterocycle and themacrocycle and the R groups attached to the carbon atoms which are bothpart of the heterocycle and the macrocycle are absent; and, optionally,one or more of R₁, R₂, R′₂, R₃, R₄, R₅, R′₅, R₆, R′₆, R₇, R₈, R₉, R′₉,and R₁₀, together with a different one of R₁, R₂, R′₂, R₃, R₄, R₅, R′₅,R₆, R′₆, R₇, R₈, R₉, R′₉, and R₁₀, which is attached to a differentcarbon atom in the macrocyclic ligand may be bound to form a straprepresented by the formula:—(CH₂)_(I)-Q-(CH₂)_(J)—R—(CH₂)_(K)—S—(CH₂)_(L)— wherein I, J, K and Lindependently are integers from 0 to 10 and Q, R and S are independentlyselected from the group consisting of alkenyl, alkenylcycloalkenyl,alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl,aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylcycloalkyl, cycloalkenylalkyl, and heterocyclyl, aza, amide,ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl,phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate,urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza, andcombinations thereof; and, optionally, one or more of R₁, R₂, R′₂, R₃,R₄, R₅, R′₅, R₆, R′₆, R₇, R₈, R₉, R′₉, and R₁₀, may be individuallybound to an atom of heterocycles U, V and W to form a strap representedby the formula:—(CH₂)_(I)-Q-(CH₂)_(J)—R—(CH₂)_(K)—S—(CH₂)_(L)— wherein I, J, K and Lindependently are integers from 0 to 10 and Q, R and S are independentlyselected from the group consisting of alkenyl, alkenylcycloalkenyl,alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl,aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylcycloalkyl, cycloalkenylalkyl, and heterocyclyl, aza, amide,ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl,phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate,urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza, andcombinations thereof; and combinations of any of the above; wherein M isa cation of a transition metal; and wherein X, Y and Z are independentlyselected from the group consisting of halide, oxo, aquo, hydroxo,alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo,ammonia, alkylamino, arylamino, heterocycloalkyl amino, heterocycloarylamino, amine oxides, hydrazine, alkyl hydrazine, aryl hydrazine, nitricoxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkylnitrile, aryl nitrile, alkyl isonitrile, aryl isonitrile, nitrate,nitrite, azido, alkyl sulfonic acid, aryl sulfonic acid, alkylsulfoxide, aryl sulfoxide, alkyl aryl sulfoxide, alkyl sulfenic acid,aryl sulfenic acid, alkyl sulfinic acid, aryl sulfinic acid, alkyl thiolcarboxylic acid, aryl thiol carboxylic acid, alkyl thiol thiocarboxylicacid, aryl thiol thiocarboxylic acid, alkyl carboxylic acid, arylcarboxylic acid, urea, alkyl urea, aryl urea, alkyl aryl urea, thiourea,alkyl thiourea, aryl thiourea, alkyl aryl thiourea, sulfate, sulfite,bisulfate, bisulfite, thiosulfate, thiosulfite, hydrosulfite, alkylphosphine, aryl phosphine, alkyl phosphine oxide, aryl phosphine oxide,alkyl aryl phosphine oxide, alkyl phosphine sulfide, aryl phosphinesulfide, alkyl aryl phosphine sulfide, alkyl phosphonic acid, arylphosphonic acid, alkyl phosphinic acid, aryl phosphinic acid, alkylphosphinous acid, aryl phosphinous acid, phosphate, thiophosphate,phosphite, pyrophosphite, triphosphate, hydrogen phosphate, dihydrogenphosphate, alkyl guanidino, aryl guanidino, alkyl aryl guanidino, alkylcarbamate, aryl carbamate, alkyl aryl carbamate, alkyl thiocarbamate,aryl thiocarbamate, alkylaryl thiocarbamate, alkyl dithiocarbamate, aryldithiocarbamate, alkylaryl dithiocarbamate, bicarbonate, carbonate,perchlorate, chlorate, chlorite, hypochlorite, perbromate, bromate,bromite, hypobromite, tetrahalomanganate, tetrafluoroborate,hexafluoroantimonate, hypophosphite, iodate, periodate, metaborate,tetraaryl borate, tetra alkyl borate, tartrate, salicylate, succinate,citrate, ascorbate, saccharinate, amino acid, hydroxamic acid,thiotosylate, and anions of ion exchange resins, or the correspondinganions thereof; or X, Y and Z are independently selected from the groupconsisting of charge-neutralizing anions which are derived from anymonodentate or polydentate coordinating ligand and a ligand system andthe corresponding anion thereof; or X, Y and Z are independentlyattached to one or more of R₁, R₂, R′₂, R₃, R₄, R₅, R′₅, R₆, R′₆, R₇,R₈, R₉, R′₉, and R₁₀; and n is an integer from 0 to
 3. 13. A method inaccordance with claim 12, wherein M is selected from the groupconsisting of Mn²⁺, Mn³⁺, Mn⁴⁺, Mn⁶⁺, Mn⁷⁺, Fe²⁺, Fe³⁺, Fe⁴⁺, Fe⁶⁺,Ni²⁺, Ni³⁺, Cu¹⁺, Cu²⁺, V²⁺, V³⁺, V⁴⁺, and V⁵⁺.
 14. A method inaccordance with claim 12, wherein M is selected from the groupconsisting of Mn²⁺, Mn³⁺, Mn⁴, Mn⁶⁺, Mn⁷⁺, Fe²⁺, Fe³⁺, Fe⁴⁺, and Fe⁶⁺.15. A method in accordance with claim 12, wherein M is Mn²⁺.
 16. Amethod in accordance with claim 12, wherein U and V are saturatedcycloalkyl heterocycles having 3 to 20 carbon atoms.
 17. A method inaccordance with claim 12, wherein U and V are saturated cycloalkylheterocycles having 4 to 10 carbon atoms.
 18. A method in accordancewith claim 12, wherein U and V are trans-cyclohexanyl fused rings.
 19. Amethod in accordance with claim 12, wherein W is a substituted orunsubstituted pyridino moiety.
 20. A method in accordance with claim 12,wherein U and V are trans-cyclohexanyl fused rings and W is asubstituted pyridino moiety.
 21. A method of treating an oral mucositisin accordance with claim 1, wherein the superoxide dismutase mimetic isa compound represented by the formula:


22. A method of treating an oral mucositis in accordance with claim 1,wherein the subject is a mammal
 23. A method of treating an oralmucositis in accordance with claim 22, wherein the mammal is a humanpatient in need thereof.
 24. A method of treating an oral mucositis inaccordance with claim 1, wherein the subject is receiving a cancertreatment.
 25. A method of treating an oral mucositis in accordance withclaim 24, wherein the cancer treatment comprises chemotherapy.
 26. Amethod of treating an oral mucositis in accordance with claim 24,wherein the cancer treatment comprises radiation therapy.
 27. A methodof treating an oral mucositis in accordance with claim 24, wherein theadministering occurs prior to the subject receiving the cancertreatment.
 28. A method of treating an oral mucositis in accordance withclaim 24, wherein the administering occurs subsequent to the subjectreceiving the cancer treatment.
 29. A method of treating an oralmucositis in accordance with claim 24, wherein the administering occurssimultaneous with the subject receiving the cancer treatment.
 30. Amethod of treating a cancer, the method comprising: a) administering toa subject in need of cancer treatment a pharmaceutical compositioncomprising a superoxide dismutase mimetic; and b) administering to thesubject an effective amount of a cancer treatment, whereby thesuperoxide dismutase mimetic prevents or reduces oral mucositis in thesubject.
 31. A method of treating a cancer in accordance with claim 30,wherein the cancer treatment comprises radiation therapy.
 32. A methodof treating a cancer in accordance with claim 30, wherein the cancertreatment comprises chemotherapy.
 33. A method of treating a cancer inaccordance with claim 30, wherein the superoxide dismutase mimetic is areactive oxygen species scavenger; and wherein the pharmaceuticalcomposition further comprises at least one additional reactive oxygenspecies scavenger.
 34. A method of treating a cancer in accordance withclaim 33, wherein the at least one additional reactive oxygen speciesscavenger is selected from the group consisting of amifostine andN-acetylcysteine.
 35. A method of treating a cancer in accordance withclaim 30, wherein the method further comprises administering apharmaceutical composition which upregulates expression of at least onetranscription factor which increases expression of one or more genescontrolling at least one naturally occurring antioxidant pathway.
 36. Amethod of treating a cancer in accordance with claim 35, wherein the atleast one transcription factor is Nrf-2
 37. A method of treating acancer in accordance with claim 35, wherein the composition whichupregulates expression of at least one transcription factor ispalifermin
 38. A method of treating a cancer in accordance with claim30, wherein the subject is a mammal
 39. A method of treating cancer inaccordance with claim 30, wherein the mammal is a human patient in needthereof.
 40. A method of treating cancer in accordance with claim 30,wherein the superoxide dismutase mimetic is a compound represented bythe formula:

wherein R₁, R′₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇, R′₇,R₈, R′₈, R₉, R′₉, R₁₀, and R′₁₀ are each independently selected from thegroup consisting of hydrogen, alkenyl, alkenylcycloalkenyl,alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl,aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylcycloalkyl, cycloalkenylalkyl, and heterocyclyl, and aralkylradicals and radicals attached to the α-carbon or α-amino acids, and—OR₁₁, —NR₁₁R₁₂, —COR₁₁, —CO₂R₁₁, —CONR₁₁R₁₂, —SR₁₁, —SOR₁₁, —SO₂R₁₁,—SO₂NR₁₁R₁₂, —N(OR₁₁)(R₁₂), —P(O)(OR₁₁)(OR₁₂), —P(O)(OR₁₁)(R₁₂),—OP(O)(OR₁₁)(OR₁₂), and substituents attached to the α-carbon of α-aminoacids, wherein R₁₁ and R₁₂ are independently hydrogen or alkyl; andoptionally, one or more of R₁ or R′₁ and R₂ or R′₂, R₃ or R′₃ and R₄ orR′₄, R₅ or R′₅ and R₆ or R′₆, R₇ or R′₇ and R₈ or R′₈, R₉ or R′₉ and R₁₀or R′₁₀ together with the carbon atoms to which they are attachedindependently form a substituted or unsubstituted and saturated,partially saturated, or unsaturated cycle or heterocycle having 3 to 20carbon atoms; and optionally, one or more of R₁ and R′₁, R₂ and R′₂, R₃and R′₃, R₄ and R′₄, R₅ and R′₅, R₆ and R′₆, R₇ and R′₇, R₈ and R′₈, R₉and R′₉, and R₁₀ and R′₁₀, together with the carbon atom to which theyare attached independently form a substituted or unsubstituted andsaturated, partially saturated, or unsaturated cycle or heterocyclehaving 3 to 20 carbon atoms; and optionally, one or more of R₁₀ or R′₁₀and R₁ or R′₁, R₂ or R′₂ and R₃ or R′₃, R₄ or R′₄ and R₅ or R′₅, R₆ orR′₆ and R₇ or R′₇, or R_(a) or R′₈ and R₉ or R′₉ together with thecarbon atoms to which they are attached independently form a substitutedor unsubstituted nitrogen containing heterocycle having 3 to 20 carbonatoms, which may be an aromatic heterocycle in which case the hydrogenattached to the nitrogen which is both part of the heterocycle and themacrocycle and the R groups attached to the carbon atoms which are bothpart of the heterocycle and the macrocycle are absent; and optionally,one or more of R₁, R′₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇,R′₇, R₈, R′₈, R₉, R′₉, R₁₀, and R′₁₀, together with a different one ofR₁, R′₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇, R′₇, R₈, R′₈,R₉, R′₉, R₁₀, and R′₁₀, which is attached to a different carbon atom inthe macrocyclic ligand may be bound to form a strap represented by theformula:—(CH₂)_(I)-Q-(CH₂)_(J)—R—(CH₂)_(K)—S—(CH₂)_(L)— wherein I, J, K and Lindependently are integers from 0 to 10 and Q, R and S are independentlyselected from the group consisting of alkenyl, alkenylcycloalkenyl,alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl,aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylcycloalkyl, cycloalkenylalkyl, and heterocyclyl, aza, amide,ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl,phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate,urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza, andcombinations thereof; and combinations of any of the above; wherein M isa cation of a transition metal; and wherein X, Y and Z are independentlyselected from the group consisting of halide, oxo, aquo, hydroxo,alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo,ammonia, alkylamino, arylamino, heterocycloalkyl amino, heterocycloarylamino, amine oxides, hydrazine, alkyl hydrazine, aryl hydrazine, nitricoxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkylnitrile, aryl nitrile, alkyl isonitrile, aryl isonitrile, nitrate,nitrite, azido, alkyl sulfonic acid, aryl sulfonic acid, alkylsulfoxide, aryl sulfoxide, alkyl aryl sulfoxide, alkyl sulfenic acid,aryl sulfenic acid, alkyl sulfinic acid, aryl sulfinic acid, alkyl thiolcarboxylic acid, aryl thiol carboxylic acid, alkyl thiol thiocarboxylicacid, aryl thiol thiocarboxylic acid, alkyl carboxylic acid, arylcarboxylic acid, urea, alkyl urea, aryl urea, alkyl aryl urea, thiourea,alkyl thiourea, aryl thiourea, alkyl aryl thiourea, sulfate, sulfite,bisulfate, bisulfite, thiosulfate, thiosulfite, hydrosulfite, alkylphosphine, aryl phosphine, alkyl phosphine oxide, aryl phosphine oxide,alkyl aryl phosphine oxide, alkyl phosphine sulfide, aryl phosphinesulfide, alkyl aryl phosphine sulfide, alkyl phosphonic acid, arylphosphonic acid, alkyl phosphinic acid, aryl phosphinic acid, alkylphosphinous acid, aryl phosphinous acid, phosphate, thiophosphate,phosphite, pyrophosphite, triphosphate, hydrogen phosphate, dihydrogenphosphate, alkyl guanidino, aryl guanidino, alkyl aryl guanidino, alkylcarbamate, aryl carbamate, alkyl aryl carbamate, alkyl thiocarbamate,aryl thiocarbamate, alkylaryl thiocarbamate, alkyl dithiocarbamate, aryldithiocarbamate, alkylaryl dithiocarbamate, bicarbonate, carbonate,perchlorate, chlorate, chlorite, hypochlorite, perbromate, bromate,bromite, hypobromite, tetrahalomanganate, tetrafluoroborate,hexafluoroantimonate, hypophosphite, iodate, periodate, metaborate,tetraaryl borate, tetra alkyl borate, tartrate, salicylate, succinate,citrate, ascorbate, saccharinate, amino acid, hydroxamic acid,thiotosylate, and anions of ion exchange resins, or the correspondinganions thereof; or X, Y and Z are independently selected from the groupconsisting of charge-neutralizing anions which are derived from anymonodentate or polydentate coordinating ligand and a ligand system andthe corresponding anion thereof; or X, Y and Z are independentlyattached to one or more of R₁, R′₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅,R₆, R′₇, R₇, R′₇, R₈, R′₈, R₉, R′₉, R₁₀, and R′₁₀; and n is an integerfrom 0 to
 3. 41. A method of treating cancer in accordance with claim30, wherein the superoxide dismutase mimetic is a compound representedby the formula:

wherein a nitrogen of the macrocycle and two adjacent carbon atoms towhich the nitrogen is attached independently form a substituted orunsubstituted, saturated, partially saturated or unsaturatednitrogen-containing heterocycle W having 2 to 20 carbon atoms, which maybe an aromatic heterocycle in which case the hydrogen attached to thenitrogen which is both part of the heterocycle and the macrocycle andthe R groups attached to the carbon atoms which are both part of theheterocycle and the macrocycle are absent; and wherein R₁, R′₁, R₂, R′₂,R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇, R′₇, R₈, R′₈, R₉, R′₉, R₁₀, andR′₁₀ are each independently selected from the group consisting ofhydrogen, alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl,alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl,cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl,cycloalkenylalkyl, and heterocyclyl, and aralkyl radicals and radicalsattached to the α-carbon or α-amino acids, and —OR₁₁, —NR₁₁R₁₂, —COR₁₁,—CO₂R₁₁, —CONR₁₁R₁₂, —SR₁₁, —SOR₁₁, —SO₂R₁₁, —SO₂NR₁₁R₁₂, —N(OR₁₁)(R₁₂),—P(O)(OR₁₁)(OR₁₂), —P(O)(OR₁)(R₁₂), —OP(O)(OR₁₁)(OR₁₂), and substituentsattached to the α-carbon of α-amino acids, wherein R₁₁ and R₁₂ areindependently hydrogen or alkyl; and, optionally, one or more of R₁ andR₂ or R′₂, R₃ or R′₃ and R₄ or R′₄, R₅ or R′₅ and R₆ or R′₆, R₇ or R′₇and R₈ or R′₈, R₉ or R′₉ and R₁₀ together with the carbon atoms to whichthey are attached independently form a substituted or unsubstituted andsaturated, partially saturated, or unsaturated cycle or heterocyclehaving 3 to 20 carbon atoms; and, optionally, one or more of R₂ and R′₂,R₃ and R′₃, R₄ and R′₄, R₅ and R′₅, R₆ and R′₆, R₇ and R′₇, R₈ and R′₈,and R₉ and R′₉, together with the carbon atom to which they are attachedindependently form a substituted or unsubstituted and saturated,partially saturated, or unsaturated cycle or heterocycle having 3 to 20carbon atoms; and, optionally, one or more of R₂ or R′₂ and R₃ or R′₃,R₄ or R′₄ and R₅ or R′₅, R₆ or R′₆ and R₇ or R′₇, or R₈ or R′₈ and R₉ orR′₉ together with the carbon atoms to which they are attachedindependently form a substituted or unsubstituted nitrogen containingheterocycle having 3 to 20 carbon atoms, which may be an aromaticheterocycle in which case the hydrogen attached to the nitrogen which isboth part of the heterocycle and the macrocycle and the R groupsattached to the carbon atoms which are both part of the heterocycle andthe macrocycle are absent; and, optionally, one or more of R₁, R′₁, R₂,R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇, R′₇, R₈, R′₈, R₉, R′₉, andR₁₀, together with a different one of R₁, R′₁, R₂, R′₂, R₃, R′₃, R₄,R′₄, R₅, R′₅, R₆, R′₆, R₇, R′₇, R₈, R′₈, R₉, R′₉, and R₁₀, which isattached to a different carbon atom in the macrocyclic ligand may bebound to form a strap represented by the formula:—(CH₂)_(I)-Q-(CH₂)_(J)—R—(CH₂)_(K)—S—(CH₂)_(L)— wherein I, J, K and Lindependently are integers from 0 to 10 and Q, R and S are independentlyselected from the group consisting of alkenyl, alkenylcycloalkenyl,alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl,aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylcycloalkyl, cycloalkenylalkyl, and heterocyclyl, aza, amide,ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl,phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate,urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza, andcombinations thereof; and optionally, one or more of R₁, R′₁, R₂, R′₂,R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇, R′₇, R₈, R′₈, R₉, R′₉, and R₁₀,may be bound to an atom of heterocycle W to form a strap represented bythe formula:—(CH₂)_(I)-Q-(CH₂)_(J)—R—(CH₂)_(K)—S—(CH₂)_(L)— wherein I, J, K and Lindependently are integers from 0 to 10 and Q, R and S are independentlyselected from the group consisting of alkenyl, alkenylcycloalkenyl,alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl,aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylcycloalkyl, cycloalkenylalkyl, and heterocyclyl, aza, amide,ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl,phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate,urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza, andcombinations thereof; and combinations of any of the above; wherein M isa cation of a transition metal; and wherein X, Y and Z are independentlyselected from the group consisting of halide, oxo, aquo, hydroxo,alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo,ammonia, alkylamino, arylamino, heterocycloalkyl amino, heterocycloarylamino, amine oxides, hydrazine, alkyl hydrazine, aryl hydrazine, nitricoxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkylnitrile, aryl nitrile, alkyl isonitrile, aryl isonitrile, nitrate,nitrite, azido, alkyl sulfonic acid, aryl sulfonic acid, alkylsulfoxide, aryl sulfoxide, alkyl aryl sulfoxide, alkyl sulfenic acid,aryl sulfenic acid, alkyl sulfinic acid, aryl sulfinic acid, alkyl thiolcarboxylic acid, aryl thiol carboxylic acid, alkyl thiol thiocarboxylicacid, aryl thiol thiocarboxylic acid, alkyl carboxylic acid, arylcarboxylic acid, urea, alkyl urea, aryl urea, alkyl aryl urea, thiourea,alkyl thiourea, aryl thiourea, alkyl aryl thiourea, sulfate, sulfite,bisulfate, bisulfite, thiosulfate, thiosulfite, hydrosulfite, alkylphosphine, aryl phosphine, alkyl phosphine oxide, aryl phosphine oxide,alkyl aryl phosphine oxide, alkyl phosphine sulfide, aryl phosphinesulfide, alkyl aryl phosphine sulfide, alkyl phosphonic acid, arylphosphonic acid, alkyl phosphinic acid, aryl phosphinic acid, alkylphosphinous acid, aryl phosphinous acid, phosphate, thiophosphate,phosphite, pyrophosphite, triphosphate, hydrogen phosphate, dihydrogenphosphate, alkyl guanidino, aryl guanidino, alkyl aryl guanidino, alkylcarbamate, aryl carbamate, alkyl aryl carbamate, alkyl thiocarbamate,aryl thiocarbamate, alkylaryl thiocarbamate, alkyl dithiocarbamate, aryldithiocarbamate, alkylaryl dithiocarbamate, bicarbonate, carbonate,perchlorate, chlorate, chlorite, hypochlorite, perbromate, bromate,bromite, hypobromite, tetrahalomanganate, tetrafluoroborate,hexafluoroantimonate, hypophosphite, iodate, periodate, metaborate,tetraaryl borate, tetra alkyl borate, tartrate, salicylate, succinate,citrate, ascorbate, saccharinate, amino acid, hydroxamic acid,thiotosylate, and anions of ion exchange resins, or the correspondinganions thereof; or X, Y and Z are independently selected from the groupconsisting of charge-neutralizing anions which are derived from anymonodentate or polydentate coordinating ligand and a ligand system andthe corresponding anion thereof; or X, Y and Z are independentlyattached to one or more of R₁, R′₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅,R₆, R′₆, R₇, R′₇, R₈, R′₈, R₉, R′₉, and R₁₀; and n is an integer from 0to
 3. 42. A method of treating cancer in accordance with claim 30,wherein the superoxide dismutase mimetic is a compound represented bythe formula:

wherein a nitrogen of the macrocycle and two adjacent carbon atoms towhich the nitrogen is attached independently form a substituted orunsubstituted, saturated, partially saturated or unsaturatednitrogen-containing heterocycle W having 2 to 20 carbon atoms, which maybe an aromatic heterocycle in which case the hydrogen attached to thenitrogen which is both part of the heterocycle and the macrocycle andthe R groups attached to the carbon atoms which are both part of theheterocycle and the macrocycle are absent; and two sets of two adjacentcarbon atoms of the macrocycle independently form substituted orunsubstituted, saturated, partially saturated or unsaturated, cycles orheterocycles U and V having 3 to 20 carbon atoms; and wherein R₁, R′₁,R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇, R′₇, R₈, R′₈, R₉, R′₉,R₁₀, and R′₁₀ are each independently selected from the group consistingof hydrogen, alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl,alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl,cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl,cycloalkenylalkyl, and heterocyclyl, and aralkyl radicals and radicalsattached to the α-carbon or α-amino acids, and —OR₁₁, —NR₁₁R₁₂, —COR₁₁,—CO₂R₁₁, —CONR₁₁R₁₂, —SR₁₁, —SOR₁₁, —SO₂R₁₁, —SO₂NR₁₁R₁₂, —N(OR₁₁)(R₁₂),—P(O)(OR₁₁)(OR₁₂), —P(O)(OR₁)(R₁₂), —OP(O)(OR₁₁)(OR₁₂), and substituentsattached to the α-carbon of α-amino acids, wherein R₁₁ and R₁₂ areindependently hydrogen or alkyl; and, optionally, one or more of R₁ andR₂ or R′₂, R₅ or R′₅ and R₆ or R′₆, R₉ or R′₉ and R₁₀ together with thecarbon atoms to which they are attached independently form a substitutedor unsubstituted and saturated, partially saturated, or unsaturatedcycle or heterocycle having 3 to 20 carbon atoms; and, optionally, oneor more of R₂ and R′₂, R₅ and R′₅, R₆ and R′₆, and R₉ and R′₉, togetherwith the carbon atom to which they are attached independently form asubstituted or unsubstituted and saturated, partially saturated, orunsaturated cycle or heterocycle having 3 to 20 carbon atoms; and,optionally, one or more of R₂ or R′₂ and R₃, R₄ and R₅ or R′₅, R₆ or R′₆and R₇, or R₈ and R₉ or R′₉ together with the carbon atoms to which theyare attached independently form a substituted or unsubstituted nitrogencontaining heterocycle having 3 to 20 carbon atoms, which may be anaromatic heterocycle in which case the hydrogen attached to the nitrogenwhich is both part of the heterocycle and the macrocycle and the Rgroups attached to the carbon atoms which are both part of theheterocycle and the macrocycle are absent; and, optionally, one or moreof R₁, R₂, R′₂, R₃, R₄, R₅, R′₅, R₆, R′₆, R₇, R₈, R₉, R′₉, and R₁₀,together with a different one of R₁, R₂, R′₂, R₃, R₄, R₅, R′₅, R₆, R′₆,R₇, R₈, R₉, R′₉, and R₁₀, which is attached to a different carbon atomin the macrocyclic ligand may be bound to form a strap represented bythe formula:—(CH₂)_(I)-Q-(CH₂)_(J)—R—(CH₂)_(K)—S—(CH₂)_(L)— wherein I, J, K and Lindependently are integers from 0 to 10 and Q, R and S are independentlyselected from the group consisting of alkenyl, alkenylcycloalkenyl,alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl,aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylcycloalkyl, cycloalkenylalkyl, and heterocyclyl, aza, amide,ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl,phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate,urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza, andcombinations thereof; and, optionally, one or more of R₁, R₂, R′₂; R₃,R₄, R₅, R′₅, R₆, R′₆, R₇, R₈, R₉, R′₉, and R₁₀, may be individuallybound to an atom of heterocycles U, V and W to form a strap representedby the formula:—(CH₂)_(I)-Q-(CH₂)_(J)—R—(CH₂)_(K)—S—(CH₂)_(L)— wherein I, J, K and Lindependently are integers from 0 to 10 and Q, R and S are independentlyselected from the group consisting of alkenyl, alkenylcycloalkenyl,alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl,aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylcycloalkyl, cycloalkenylalkyl, and heterocyclyl, aza, amide,ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl,phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate,urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza, andcombinations thereof; and combinations of any of the above; wherein M isa cation of a transition metal; and wherein X, Y and Z are independentlyselected from the group consisting of halide, oxo, aquo, hydroxo,alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo,ammonia, alkylamino, arylamino, heterocycloalkyl amino, heterocycloarylamino, amine oxides, hydrazine, alkyl hydrazine, aryl hydrazine, nitricoxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkylnitrile, aryl nitrile, alkyl isonitrile, aryl isonitrile, nitrate,nitrite, azido, alkyl sulfonic acid, aryl sulfonic acid, alkylsulfoxide, aryl sulfoxide, alkyl aryl sulfoxide, alkyl sulfenic acid,aryl sulfenic acid, alkyl sulfinic acid, aryl sulfinic acid, alkyl thiolcarboxylic acid, aryl thiol carboxylic acid, alkyl thiol thiocarboxylicacid, aryl thiol thiocarboxylic acid, alkyl carboxylic acid, arylcarboxylic acid, urea, alkyl urea, aryl urea, alkyl aryl urea, thiourea,alkyl thiourea, aryl thiourea, alkyl aryl thiourea, sulfate, sulfite,bisulfate, bisulfite, thiosulfate, thiosulfite, hydrosulfite, alkylphosphine, aryl phosphine, alkyl phosphine oxide, aryl phosphine oxide,alkyl aryl phosphine oxide, alkyl phosphine sulfide, aryl phosphinesulfide, alkyl aryl phosphine sulfide, alkyl phosphonic acid, arylphosphonic acid, alkyl phosphinic acid, aryl phosphinic acid, alkylphosphinous acid, aryl phosphinous acid, phosphate, thiophosphate,phosphite, pyrophosphite, triphosphate, hydrogen phosphate, dihydrogenphosphate, alkyl guanidino, aryl guanidino, alkyl aryl guanidino, alkylcarbamate, aryl carbamate, alkyl aryl carbamate, alkyl thiocarbamate,aryl thiocarbamate, alkylaryl thiocarbamate, alkyl dithiocarbamate, aryldithiocarbamate, alkylaryl dithiocarbamate, bicarbonate, carbonate,perchlorate, chlorate, chlorite, hypochlorite, perbromate, bromate,bromite, hypobromite, tetrahalomanganate, tetrafluoroborate,hexafluoroantimonate, hypophosphite, iodate, periodate, metaborate,tetraaryl borate, tetra alkyl borate, tartrate, salicylate, succinate,citrate, ascorbate, saccharinate, amino acid, hydroxamic acid,thiotosylate, and anions of ion exchange resins, or the correspondinganions thereof; or X, Y and Z are independently selected from the groupconsisting of charge-neutralizing anions which are derived from anymonodentate or polydentate coordinating ligand and a ligand system andthe corresponding anion thereof; or X, Y and Z are independentlyattached to one or more of R₁, R₂, R′₂, R₃, R₄, R₅, R′₅, R₆, R′₆, R₇,R₈, R₉, R′₉, and R₁₀; and n is an integer from 0 to
 3. 43. A method oftreating cancer in accordance with claim 30, wherein the superoxidedismutase mimetic is a compound represented by the formula:


44. A kit comprising a superoxide dismutase mimetic and at least oneadditional pharmaceutical compound selected from the group consisting ofa chemotherapeutic agent and a non-superoxide dismustase mimetic radicalscavenger.
 45. A kit in accordance with claim 44, further comprisinginstructions for administering the superoxide dismutase mimetic to asubject in need of amelioration of oral mucositis resulting from acancer therapy.
 44. A kit comprising a superoxide dismutase mimetic andat least one additional pharmaceutical compound selected from the groupconsisting of a chemotherapeutic agent and a non-superoxide dismustasemimetic radical scavenger.
 45. A kit in accordance with claim 44,further comprising instructions for administering the superoxidedismutase mimetic to a subject in need of amelioration of oral mucositisresulting from a cancer therapy.
 46. A kit in accordance with claim 44,wherein the chemotherapeutic agent is selected from a group consistingof all-trans retinoic acid, azacitidine, azathioprine, bleomycin,carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide,cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin,epirubicin, epothilone, etoposide, fluorouracil, gemcitabine,hydroxyurea, idarubicin, imatinib, mechlorethamine, mercaptopurine,methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed,teniposide, tiguanine, valrubicin, vinblastine, vincristine, vindesine,vinorelbine.
 47. A kit in accordance with claim 44, wherein thenon-superoxide dismutase mimetic radical scavenger is selected from thegroup consisting of amifostine and N-acetylcysteine.
 48. A kit inaccordance with claim 44, wherein the superoxide dismutase mimetic is acompound represented by the formula:

wherein R₁, R′₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇, R′₇,R₈, R′₈, R₉, R′₉, R₁₀, and R′₁₀ are each independently selected from thegroup consisting of hydrogen, alkenyl, or R′₅ and R₆ or R′₆, R₇ or R′₇and R₈ or R′₈, R₉ or R′₉ and R₁₀ or R′₁₀ together with the carbon atomsto which they are attached independently form a substituted orunsubstituted and saturated, partially saturated, or unsaturated cycleor heterocycle having 3 to 20 carbon atoms; and optionally, one or moreof R₁ and R′₁, R₂ and R′₂, R₃ and R′₃, R₄ and R′₄, R₅ and R′₅, R₆ andR′₆, R₇ and R′₇, R₈ and R′₈, R₉ and R′₉, and R₁₀ and R′₁₀, together withthe carbon atom to which they are attached independently form asubstituted or unsubstituted and saturated, partially saturated, orunsaturated cycle or heterocycle having 3 to 20 carbon atoms; andoptionally, one or more of R₁₀ or R′₁₀ and R₁ or R′₁, R₂ or R′₂ and R₃or R′₃, R₄ or R′₄ and R₅ or R′₅, R₆ or R′₆ and R₇ or R′₇, or R₈ or R′₈and R₉ or R′₉ together with the carbon atoms to which they are attachedindependently form a substituted or unsubstituted nitrogen containingheterocycle having 3 to 20 carbon atoms, which may be an aromaticheterocycle in which case the hydrogen attached to the nitrogen which isboth part of the heterocycle and the macrocycle and the R groupsattached to the carbon atoms which are both part of the heterocycle andthe macrocycle are absent; and optionally, one or more of R₁, R′₁, R₂,R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇, R′₇, R₈, R′₈, R₉, R′₉, R₁₀,and R′₁₀, together with a different one of R₁, R′₁, R₂, R′₂, R₃, R′₃,R₄, R′₄, R₅, R′₅, R₆, R′₆, R₇, R′₇, R₈, R′₈, R₉, R′₉, R₁₀, and R′₁₀,which is attached to a different carbon atom in the macrocyclic ligandmay be bound to form a strap represented by the formula:—(CH₂)_(I)-Q-(CH₂)_(J)—R—(CH₂)_(K)—S—(CH₂)_(L)— wherein I, J, K and Lindependently are integers from 0 to 10 and Q, R and S are independentlyselected from the group consisting of alkenyl, alkenylcycloalkenyl,alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl,aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylcycloalkyl, cycloalkenylalkyl, and heterocyclyl, aza, amide,ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl,phosphinyl, phosphino, phosphonium, keto, ester, alcohol, carbamate,urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza, andcombinations thereof; and combinations of any of the above; wherein M isa cation of a transition metal; and wherein X, Y and Z are independentlyselected from the group consisting of halide, oxo, aquo, hydroxo,alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo,ammonia, alkylamino, arylamino, heterocycloalkyl amino, heterocycloarylamino, amine oxides, hydrazine, alkyl hydrazine, aryl hydrazine, nitricoxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkylnitrile, aryl nitrile, alkyl isonitrile, aryl isonitrile, nitrate,nitrite, azido, alkyl sulfonic acid, aryl sulfonic acid, alkylsulfoxide, aryl sulfoxide, alkyl aryl sulfoxide, alkyl sulfenic acid,aryl sulfenic acid, alkyl sulfinic acid, aryl sulfinic acid, alkyl thiolcarboxylic acid, aryl thiol carboxylic acid, alkyl thiol thiocarboxylicacid, aryl thiol thiocarboxylic acid, alkyl carboxylic acid, arylcarboxylic acid, urea, alkyl urea, aryl urea, alkyl aryl urea, thiourea,alkyl thiourea, aryl thiourea, alkyl aryl thiourea, sulfate, sulfite,bisulfate, bisulfite, thiosulfate, thiosulfite, hydrosulfite, alkylphosphine, aryl phosphine, alkyl phosphine oxide, aryl phosphine oxide,alkyl aryl phosphine oxide, alkyl phosphine sulfide, aryl phosphinesulfide, alkyl aryl phosphine sulfide, alkyl phosphonic acid, arylphosphonic acid, alkyl phosphinic acid, aryl phosphinic acid, alkylphosphinous acid, aryl phosphinous acid, phosphate, thiophosphate,phosphite, pyrophosphite, triphosphate, hydrogen phosphate, dihydrogenphosphate, alkyl guanidino, aryl guanidino, alkyl aryl guanidino, alkylcarbamate, aryl carbamate, alkyl aryl carbamate, alkyl thiocarbamate,aryl thiocarbamate, alkylaryl thiocarbamate, alkyl dithiocarbamate, aryldithiocarbamate, alkylaryl dithiocarbamate, bicarbonate, carbonate,perchlorate, chlorate, chlorite, hypochlorite, perbromate, bromate,bromite, hypobromite, tetrahalomanganate, tetrafluoroborate,hexafluoroantimonate, hypophosphite, iodate, periodate, metaborate,tetraaryl borate, tetra alkyl borate, tartrate, salicylate, succinate,citrate, ascorbate, saccharinate, amino acid, hydroxamic acid,thiotosylate, and anions of ion exchange resins, or the correspondinganions thereof; or X, Y and Z are independently selected from the groupconsisting of charge-neutralizing anions which are derived from anymonodentate or polydentate coordinating ligand and a ligand system andthe corresponding anion thereof; or X, Y and Z are independentlyattached to one or more of R₁, R′₁, R₂, R′₂, R₃, R′₃, R₄, R′₄, R₅, R′₅,R₆, R′₆, R₇, R′₇, R₈, R′₈, R₉, R′₉, R₁₀, and R′₁₀; and n is an integerfrom 0 to
 3. 49. A kit in accordance with claim 44, wherein thesuperoxide dismutase mimetic is a compound represented by the formula: